Review

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Role of the CD4 count in HIV management

As a result of successful antiretroviral treatment over the last 20 years, HIV has become more of a chronic disease
for practitioners to manage, requiring careful, but routine, clinical monitoring. Laboratory markers, such as the
HIV-1 RNA viral load and CD4 cell count, are regularly used for patient management in addition to predicting
disease progression and/or treatment outcomes. The HIV viral load is considered to be the gold standard for
evaluating treatment success, although it is often limited by the cost. Furthermore, in certain cases, there is a
mismatch between an undetectable viral load (<50 copies/ml) and the absence of immune reconstitution, which
can be confusing to both the treatment provider and patient. In this review, the utility of the CD4 count as a
predictor for HIV disease progression in patients not on therapy is evaluated, as well as a method for monitoring
a patient’s response to therapy. Its use in predicting immune reconstitution in patients initiating antiretrovirals is
also identified. We hope to aid the clinician by examining the most recent literature and discussing the added value
of the CD4 count in the management of a person with HIV infection.

KEYWORDS: antiretroviral treatment n CD4 count n CD4 percentage n discordance Jennifer Hoffman1,
n HIV n IRIS n management n predictor n resource-limited settings Johan van Griensven2 ,
Robert Colebunders2,3
& Mehri McKellar1†
†
Author for correspondence:
Medscape: Continuing Medical Education Online 1
Duke University,
DUMC 102359, Durham,
This activity has been planned and implemented in accordance with the Essential Areas and NC 27710, USA
policies of the Accreditation Council for Continuing Medical Education through the joint Tel.: +1 919 613 6129;
sponsorship of MedscapeCME and Future Medicine Ltd. MedscapeCME is accredited by the Fax: +1 919 684 8902;
Accreditation Council for Continuing Medical Education (ACCME) to provide continuing mehri.mckellar@duke.edul
medical education for physicians. MedscapeCME designates this educational activity for a 2
Prince Leopold Institute for
maximum of 0.75 AMA PRA Category 1 Credits™. Physicians should only claim credit Tropical Medicine,
commensurate with the extent of their participation in the activity. All other clinicians completing Antwerp, Belgium
this activity will be issued a certificate of participation. To participate in this journal CME
3
University of Antwerp,
Belgium
activity: (1) review the learning objectives and author disclosures; (2) study the education content;
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Learning objectives
Upon completion of this activity, participants should be able to:
n List the advantages of using the CD4 count in the management of patients with HIV infection

n Employ CD4 counts effectively in the management of patients with HIV infection

n Identify relationships between CD4 counts and other means to monitor the progress of

HIV infection
n Specify clinical outcomes associated with the CD4 count

10.2217/HIV.09.58 © 2010 Future Medicine Ltd HIV Ther. (2010) 4(1), 27–39 ISSN 1758-4310 27
Review | Hoffman, van Griensven, Colebunders & McKellar
Financial & competing interests disclosure
CME Author: Charles P Vega, MD, Associate Professor; Residency Director, Department of Family Medicine, University
of California, Irvine, USA. Disclosure: Charles P Vega, has disclosed no relevant financial relationships.
Editor: Elisa Manzotti, Editorial Director, Future Science Group. Disclosure: Elisa Manzotti has disclosed no relevant
financial relationships.
Authors and Credentials: Jennifer Hoffman, MD, Duke University Medical Center, Durham, NC, USA. Disclosure:
Jennifer Hoffman has no relevant affiliations or financial involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment,
consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Johan van Griensven, MD, PhD, Prince Leopold Institute for Tropical Medicine, Antwerp, Belgium. Disclosure: Johan
van Griensven received support from the Inbev-Baillet Latour Fund (private donation not related to a pharmaceutical
company). The author has no other relevant affiliations or financial involvement with any organization or entity with a
financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those
disclosed. No writing assistance was utilized in the production of this manuscript.
Robert Colebunders, MD, PhD, Prince Leopold Institute for Tropical Medicine, Antwerp, Belgium. Disclosure: Robert
Colebunders received grants from Abbott, Tibotec Therapeutics, Pfizer, Bristol-Meyers Squibb, Roche, GlaxoSmithKline,
Gilead and Merck. The author has no other relevant affiliations or financial involvement with any organization or entity
with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from
those disclosed. No writing assistance was utilized in the production of this manuscript.
Mehri McKellar, MD, Duke University Medical Center, Durham, NC, USA. Disclosure: Mehri McKellar received a
research grant from Tibotec Therapeutics. The author has no other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the

Morbidity and mortality from HIV/AIDS
has declined both in the USA, as well as other
developed countries, and in developing nations
since the advent of HAART [1,2,101] . In clinical
trials, different HAART regimens have been
found to produce viral suppression in up to
80–90% of subjects [3,4] . However, the long-
term durability of potent HAART in clini-
cal practice is not entirely clear. Success rates
of clinical trials are not easily translated into
clinical practice, and treatment outcomes in
a clinic setting have been shown to be worse
than those in research trials [3,5] . Treatment
failure, whether attributable to virologic fail-
ure, stopping HAART or loss to follow-up,
leads to increases in morbidity and mortal-
ity [6,7] . Having a reliable marker to evaluate
disease progression and predict treatment out-
comes would be useful for the practitioner and
patient alike.
Since the introduction of HAART, much has
been studied regarding which factors best pre-
dict a patient’s success on HAART. Previously
described predictors of treatment failure include
poor adherence to medications, one or more
missed visits in the previous year, prior virologic
failure, a regimen consisting only of nucleo-
sides, higher baseline viral loads and lower
baseline CD4 cell counts [3,5,8–10] . Scoring
systems have been designed and validated to
assess the incidence of clinical disease progres-
sion among patients receiving HAART. In a
model designed by the EuroSIDA study group,
the most recent CD4 cell count, viral load and
hemoglobin level were independently related
to the risk of disease progression, as was a late
presentation of persons with advanced disease,
before the start of HAART [11] .
Several cohort studies and clinical trials have
shown that the CD4 count is the strongest pre-
dictor of subsequent disease progression and
survival [12,13] . The use of the CD4 count as an
independent and reliable marker for treatment
outcome is attractive from various aspects. First,
CD4 counts are already the most important fac-
tor in deciding whether to initiate antiretro­viral
therapy and opportunistic prophylaxis – all
HIV-positive patients in high-income coun-
tries, and an increasing number of patients
in low-income countries have a baseline CD4
count at entry into care [102] . Second, the CD4
count is a relatively objective and simple marker
to follow. Finally, the cost of CD4 counts has
become more affordable, including in develop-
ing countries [14,15] . This article further evalu-
ates the use of the CD4 count in assessing the
clinical status of HIV-infected individuals, in
making informed decisions regarding the initia-
tion of antiretroviral therapy and in ­monitoring
the ­success of such therapy.

28 HIV Ther. (2010) 4(1) future science group


What is an adequate CD4 response
on HAART?
An adequate CD4 response for most patients on
therapy is defined as an increase in the range of
50–150 cells/mm3 per year with an accelerated
response in the first 3 months of treatment [102] .
In general, CD4 counts should be checked
every 3–4 months to determine when to start
anti­retroviral therapy, to assess immunologic
response to therapy and to evaluate the need for
initiation or discontinuation of prophylaxis for
opportunistic infections (OIs). Patients with
good virologic control average approximately
50–100 cells/mm3 per year until a steady-state
level is reached [102] . A clinically significant
change between CD4 counts approximates a
30% change in the absolute count or an increase
or decrease in CD4 percentage by 3% [102] .
For those patients who adhere to therapy with
sustained viral suppression and are clinically
stable for more than 2–3 years, the frequency
of CD4 count monitoring may be extended to
every 6 months. In cases of discordant CD4
and viral-load results, the clinician should first
exclude a laboratory error and consider retesting
the patient.
Absolute CD4 counts may fluctuate among
individuals or be influenced by factors that affect
the total white blood cell count and lymphocyte
percentages (Box 1) . Bone marrow-suppressive
medications and IFN‑a may reduce the abso-
lute CD4 count [16,103] . Acute infection, sepsis,
malaria and TB can decrease both absolute
CD4 counts and percentages [17–19,103] . In turn,
a splenectomy or co-infection with human T‑cell
leukemia virus type 1 may cause misleadingly
elevated absolute CD4 counts [20,21] . Although it
does not appear to yield clinical effects, adminis-
tration of IL‑2 has been shown to increase CD4
counts [22–24] ; and steroids can both increase
and decrease CD4 counts [25,103] . Sex, race and
psychological and physical stress typically have a
minimal effect on CD4 counts [103] . Pregnancy
can lead to hemodilution with a small decline in
CD4 count but no decline in percentage [103] . In
many of these cases, the CD4 percentage remains
stable and may be a more appropriate parameter
to assess the patient’s immune function.
Baseline CD4 count as a
predictor of disease progression
& treatment outcome
Numerous studies have demonstrated that the
baseline CD4 count serves as a significant prog-
nostic indicator for treatment outcome [5,12,26–29] .
future science group
Role of the CD4 count in HIV management | Review
In one study, patients starting therapy with a
CD4 count below 200 cells/mm3 were almost
twice as likely (HR: 1.90) to fail treatment,
compared with those starting with a CD4 count
higher than 200 cells/mm3 [5] . Another study
showed an inverse relationship between the CD4
count at baseline and a risk of progression to
AIDS or death [12] . This effect was quite dra-
matic: the adjusted HR for progression to AIDS
or death was 0.24 (95% CI: 0.20–0.30) for
patients starting HAART with a baseline CD4
count of 200–350 cells/mm3, compared with
patients with a CD4 count below 50 cells/mm3.
Recent data support the prognostic value at
higher CD4 cell-count levels. In a large cohort
study, patients initiating HAART with CD4
counts of 350–500 cells/mm 3 had a 94%
increased risk of death, relative to those with
baseline CD4 counts above 500 cells/mm3 [30] .
Equally, this and another study documented
an increased risk of death when HA ART
was deferred until the CD4 count fell below
350 cells/mm 3 [30,31] . These studies and oth-
ers have renewed and validated the impetus for
earlier treatment of HIV.
A similarly strong association has been
observed between the baseline CD4 count and
the subsequent CD4 response on HAART ther-
apy [26–28,32] . These studies demonstrate that
individuals with the highest baseline CD4 count
at HAART initiation have the best chance for
full immune reconstitution and restoration of
a near-normal CD4 count and support a higher
CD4 thres­hold for HAART initiation. In the
ACTG 384 study, immune reconstitution was
evaluated for five different baseline CD4 strata
(<50 to >500 cells/mm3) [32] . Although abso-
lute CD4 count increases were similar in all
strata, only patients in the higher baseline strata
Box 1. Factors influencing CD4 counts.
Factors that decrease CD4 counts
„„ Corticosteroids
„„ Interferon (including pegylated)
„„ Chemotherapy
„„ Acute infection
„„ Sepsis
„„ Malaria
„„ TB
Factors that increase CD4 counts
„„ Corticosteroids
„„ IL‑2
„„ Splenectomy
„„ Human T‑cell leukemia virus type 1
Data taken from [16–25,103].
www.futuremedicine.com 29
Review | Hoffman, van Griensven, Colebunders & McKellar
achieved close to normal CD4 values following
3 years of HAART. In addition, abnormalities in
CD4 naive-memory cell-count ratios and T‑cell
activation markers were clearly more pronounced
in the lower CD4 strata, although immune
imbalances remained among all patients. The
ACTG 384 study suggests that T‑cell subsets
and ratios may give more detailed prognostic
information on immune recovery on HAART
than absolute CD4 counts [32] . Importantly,
some of these activation markers have already
been strongly linked with disease progression [33] .
Several recent studies have focused on the prog-
nostic value of inflammatory (e.g., high-sensitiv-
ity C-reactive protein and IL‑6) and coagulation
markers (e.g., d-dimer). Increasingly, it is becom-
ing clear that elevated levels of these markers are
predictive of overall mortality and AIDS- and
non-AIDS-related events, independent of CD4
counts or viral-load values [34–38] .
The importance of the baseline CD4 count
also holds true in low-income countries; the
Antiretroviral Treatment in Lower-Income
Countries (ART-LINC) collaborative has shown
that the most important predictor of a patient’s
CD4 response on HAART is the baseline CD4
count at the time treatment is initiated [39] .
However, it should be noted that substantial
improvements in CD4 counts often occur
even in patients who are profoundly immuno-
suppressed at the time of HAART initiation.
A study in Cambodia, involving 416 patients
with a median CD4 count of 11 cells/mm3 at
the time of HAART initiation, showed that
an impressive 74% had achieved CD4 counts
higher than 200 cells/mm3 24 months later [40] .
Although very low baseline CD4 counts are a
risk factor for inadequate CD4 reconstitution
on HAART, many patients will still manage to
achieve a CD4 count above the critical thres­
hold of 200 cells/mm3 after a period of time on
HAART with successful ­virologic suppression.
Recovery of CD4 cells as a prognostic
marker for patients on HAART
The extent of recovery of CD4 cells, once the
patient has been placed on HAART, appears to
be another important predictor of treatment suc-
cess; patients who achieve close to normal values
could potentially have a normal lifespan [41] . Most
studies focus on reducing AIDS-related mortality
with progressive increases in CD4 counts while
on treatment. Among previously HAART-naive
patients, those who obtain CD4 counts between
500–649 cells/mm3 had a 55% higher risk of
30 HIV Ther. (2010) 4(1)
AIDS or death compared with those with values
of at least 650 cells/mm3 [42] . However, several
studies have clearly illustrated that at higher CD4
counts non-AIDS-related diseases, specifically
malignancies, cardiovascular, liver and kidney
disease, account for the majority of deaths [43] .
In a recent study by Marin et al., the risk
of non-AIDS-defining deaths was reduced by
approximately 30% for non-AIDS infections,
end-stage liver disease and non-AIDS malignan-
cies for each 100 cell/mm3 increment in the latest
CD4 count [44] . Similar data has been reported
in other studies [45–47] . A fascinating study
by Gutierrez et al. demonstrated that among
patients starting HAART with sustained viro-
logic suppression, immunologic nonresponders
(defined in this study as a <50 cells/mm3 increase
in CD4 counts after 1 year on HAART) had
more than a four-times greater rate of non-AIDS-
related death, compared with those with satisfac-
tory immunologic responses [48] . All together,
these findings suggest that subclinical immuno­
deficiency may be related with long-term risks,
both AIDS and non-AIDS related. In line with
this, the recent US Department of Health and
Human Services guidelines recommend defining
immuno­logical failure as the lack of an increase
in CD4 counts to more than 350–500 cells/mm3
after 4–7 years of effective HAART [102] .
Absolute CD4 count versus
CD4 percentage
Several studies listed in Table 1 have shown the
utility of the CD4 percentage in providing addi-
tional information about prognosis and when to
initiate antiretroviral therapy. The CD4 percent
appears to be most useful in patients with CD4
counts above 200 cells/mm3. One cohort study
by Moore et al. demonstrated that in patients
starting HAART with an absolute CD4 count
of 200–350 cells/mm 3, a CD4 percentage of
less than 15% was associated with a markedly
increased risk of mortality (relative hazard
[RH]: 2.71), in comparison to those subjects with
a similar baseline CD4 count but a CD4 percent-
age above 15% [49] . Another retrospective cohort
study by Pirzada et al. demonstrated that CD4
percentage is superior to absolute CD4 counts
in predicting time to an AIDS-related event,
including for patients not yet on HAART with
CD4 counts between 200–350 cells/mm3 [50] .
A third study by Guiguet et al. demonstrated
that CD4 percentage has additional prognos-
tic values in terms of progression to an AIDS-
defining event or death in patients with a CD4
future science group
 Role of the CD4 count in HIV management | Review

Table 1. CD4 count versus CD4 percentage as a predictor of outcomes.

Study design Study population Outcomes Conclusion Ref.
examined
Population-based 1623 antiretroviral Survival CD4 percentage [49]
cohort study treatment-naive independently predicts
HIV+ individuals survival in patients with
initiating HAART CD4 counts of
200–350 cells/mm3
Retrospective 218 HIV patients,
+
AIDS-related events CD4 percentage is the best [50]
cohort approximately half on predictor of AIDS-related
HAART and half not on events when the CD4
HAART count is between
200–350 cells/mm3, but
absolute CD4 count is
superior when the CD4
count is <200 cells/mm3
Prospective cohort 9740 HIV antiretroviral AIDS-defining events CD4 percentage, in
+
[51]
treatment-naive patients and death addition to absolute CD4
with a CD4 count of count, adds prognostic
>200 cells/mm3 and not value for predicting
meeting other criteria AIDS-defining events, but
for diagnosis of AIDS not for predicting death
Prospective cohort 788 HIV+ patients ‘Disease progression’ CD4 percentage [52]
initiating HAART as defined by new independently predicts
opportunistic disease progression in
infections, other patients initiating HAART
AIDS-defining events with a CD4 count of
or death >350 cells/mm3

count of 350–500 cells/mm3 ; patients with an only’, without an appropriate immunological

absolute CD4 count in this range but a CD4
percentage below 15%, were found to be at risk
for an AIDS-defining event or death similar to
that of patients with an absolute CD4 count of
200–350 cells/mm3 but a CD4 percentage of
over 15% [51] . A study by Hulgan et al. demon-
strated that patients with an absolute CD4 count
of over 350 cells/mm3 and a CD4 percent below
17% had earlier disease progression, compared
with those with a CD4 percent above 17% [52] .
It is somewhat surprising that CD4 percentage
adds such predictive value even in patients with
absolute CD4 counts above 350 cells/mm 3.
Some of the additional value of the CD4 per-
centage may be due to the fact that absolute CD4
counts vary depending on the time of day and
other factors (e.g., in acute infection) – CD4
percentage is less subject to this variability [50] .
However, absolute CD4 count continues to be
the superior prognostic indicator for patients
with CD4 counts lower than 200 cells/mm3 [50] .
Discordant CD4 count & HIV-1
viral load
Even though definitions of immunologic suc-
cess vary between studies, individuals with
discordant responses on HAART (‘virological
response, or ‘immunologic only’ without viral
suppression) consistently do worse than indi-
viduals with complete responses (both virologi-
cal and immunological), yet generally do better
than those with no response. One observational,
multicenter study found that after 4 years of
follow-up, the rate of clinical disease progres-
sion was six-times greater in nonresponders,
1.9-times greater in virologic-only responders
and 2.3-times greater in immunologic-only
responders. However, patients with virologic-
only response or with immunologic-only
response had a significantly reduced risk for
clinical progression than nonresponders [53] .
Other studies have demonstrated similar out-
comes, with discordant responses being signifi-
cantly associated with an earlier development of
an OI or death [54] .
An interesting study by Tan et al. examined
a group of treatment-naive patients starting on
HAART between 1995 and 2004 [54] . Among
these patients, 70% experienced a complete
response, 16% experienced an immunologic-
only response, 9% had a virologic-only response
and 5% had a concordant unfavorable response
(neither viral suppression nor an increase of
>50 cells/mm 3 in CD4 count). Patients who

future science group www.futuremedicine.com 31

Review | Hoffman, van Griensven, Colebunders & McKellar
experienced discordant virologic and immu-
nologic responses had a RH of 2.28 for the
development of an OI or death, compared
with those with a complete response; those
in the nonresponse group had an RH of 4.83
for the development of OI or death, compared
with the complete response group. Similarly,
a study by Moore et al. demonstrated that a
discordant immunologic and virologic response
was an independent risk factor for mortality
(RH: 1.87) [55] .
„„Adequate immunological
response despite virological failure
(immunologic only)
Risk factors for immunologic-only response
include younger age, a lower baseline CD4
count, higher baseline viral load, poor adher-
ence to therapy and antiretroviral drug resis-
tance (Box 2) [53,55–58] . Although the underlying
mechanism is not entirely understood, less doubt
exists on the management of this type of discor-
dant response. Since current guidelines strongly
emphasize the need to achieve undetectable viral
loads, treatment change is usually recommended
unless treatment options are limited or other
underlying causes can be identified.
„„Poor immunological response despite
effective virological response (virologic only)
Most studies have indicated that patients
starting on HA ART with a lower baseline
CD4 count are more likely to develop a viro-
logic-only response, probably related to dis-
turbances in regulatory functions over T‑cell
homeostasis [59,60] . In addition, older age also
seems to be associated with a lower degree
of immune reconstitution, even with suc-
cessful viral suppression (Box 2) [28,56] . Some
data have demonstrated that this is related
to a decreased thymic activity in older indi-
viduals [53,55,56] . Other risk factors for an
Box 2. Risk factors for discordant HIV-1 viral load and CD4 responses.
Factors associated with immunologic-only response
„„ Lower baseline CD4 count
„„ Younger age
„„ Higher baseline viral load
„„ Poor adherence to therapy
„„ Multidrug resistance virus
Factors associated with virologic-only response
„„ Lower baseline CD4 count
„„ Older age
„„ Use of tenofovir/didanosine-containing regimens
Data taken from [28,53,55–58].
32 HIV Ther. (2010) 4(1)
inadequate immunologic response may include
the use of didanosine/tenofovir‑containing
­regimens [57,58] .
The pathophysiologic reason for failure to
reconstitute a normal CD4 T‑cell population
despite sustained virologic suppression is an
area of ongoing investigation. Several stud-
ies have found that genetic polymorphisms,
including the Fas receptor (CD95) gene, the
Fas ligand (CD178), the IL‑6 gene, and the
MHC genes are involved in T‑cell immunity
and affect whether an individual experiences
an immunologic response to HAART therapy
or not [61,62] . Some investigators have asserted
that the lack of reconstitution may be related
to increased chronic T‑cell activation, higher
levels of T‑cell apoptosis and a lower production
of naive T cells [63] . A recent study by Marziali
et al. showed that immunologic nonresponders
to HAART (defined as those who experienced
<20% increase in CD4 count, or an abso-
lute count <200 cells/mm 3 following at least
1 year of therapy) differed from immunologic
responders in several ways: reduced numbers of
naive and thymic T cells, higher levels of IL‑7
indicating persistent immune activation, lower
numbers of regulatory T cells and a reduced
expression of the IL‑7 receptor (IL‑7Ra) on
CD4 and CD8 T cells [64] . A recent, intriguing
case series by Nies-Kraske et al. suggests that
fibrosis of the T‑cell zone of lymphoid tissue
may also be an important factor in the failure
to reconstitute T cells [65] . Together, these find-
ings demonstrate that the immune systems of
immunologic nonresponders may differ from
those of individuals with a successful immune
response to HAART.
CD4 count & immune reconstitution
inflammatory syndrome
The development of immune reconstitution
inflammatory syndrome (IRIS) can occur in
the first weeks to months following HAART
initiation, particularly among patients with a
co-existing OI [66] . IRIS occurs as the immune
system is reconstituted during the early period
on HAART and is caused by a pathologic
immune response to a latent or active infec-
tion, which leads to increased inflammatory
symptoms. This can occur in response to any
infection; however, some of the most com-
mon ones include Mycobacterium tuberculosis,
other mycobacterial infections, herpes zoster,
cytomegalovirus, Pneumocystis (carinii) jiroveci
pneumonia and Cryptococcus neoformans [66,67] .
future science group

CD4 count and CD4 percentage before start-
ing HAART have been shown to be important
risk factors in determining which patients
develop IRIS after the initiation of HAART. One
cohort study of an ethnically diverse population
starting on HAART demonstrated that a CD4
percentage of less than 15% was associated with
a greater risk of development of IRIS by nearly
three-times compared with a CD4 percentage
over 15% (OR: 2.97 for a CD4 percentage >10%,
and 2.59 for a CD4 percentage of 10–15%) [68] .
A recent case-control study at Johns Hopkins
University Hospital (MD, USA) revealed that a
CD4 count of under 100 cells/mm3 was a strong
independent risk factor for the development of
IRIS (OR: 6.2) [67] . Other studies have shown
similar associations between a lower nadir CD4
count and a higher risk of developing IRIS [69] .
The rate of the increase of CD4 count after ini-
tiation of HAART may also be a risk factor in
the development of IRIS, with patients who have
a more rapid rise in CD4 count being at a higher
risk for developing IRIS [66] ; however, not all
studies have confirmed this.
CD4 count monitoring in
resource-limited settings
One of the many challenges in deciding when to
start and how to monitor patients on HAART in
resource-limited settings (RLS) is the inaccessi-
bility and expense of laboratory tests, including
CD4 counts and viral load, which are standard
of care in the developed world. Since viral-load
testing is not widely available, the WHO has
developed clinical and immunologic criteria that
can be used to define treatment failure in RLS.
Clinical failure is defined as the development
of a new or recurrent WHO stage 4 condition.
Immunologic failure is defined as a persistent
CD4 count of under 100 cells/mm3, a fall in
CD4 count of more than 50% from the on-
treatment peak value or a fall in CD4 count
to below the pretreatment value [104] . Since in
some locations the availability of CD4 testing
is limited, numerous researchers have looked
at whether the total lymphocyte count (TLC)
can be used as a surrogate marker for CD4
counts with variable results. The correlation
between TLC and CD4 appears to be poor
in children [70] . The correlation in adults may
be slightly better; one study of HIV-infected
patients in Nairobi, Kenya found that a TLC
cut-off of 1900 cells/mm 3 was 81% sensitive
and 90% specific in detecting patients with a
CD4 count below 200 cells/mm3 [71] . Another
future science group
Role of the CD4 count in HIV management | Review
study in Ethiopia found that a TLC cutoff of
1780 cells/mm3 was 61% sensitive and 62% spe-
cific in identifying adults with a CD4 count of
less than 200 cells/mm3 [72] . The TLC generally
increases while on HAART but is not a reliable
test to monitor the efficacy of such treatment.
Recently, there has been a great deal of effort
towards finding simpler and more cost-effective
means of measuring CD4 counts. Novel tech-
niques have been devised, utilizing more afford-
able flow cytometry methods as well as technol-
ogies other than flow cytometry, which requires
significant operator expertise in addition to the
expense [73–75] . One promising technology is the
modified Dynabeads® method for measuring
CD4 counts; the cost for this test is less than
US$3/sample, compared with $17/sample for
the older Capcellia technology [73,74] .
Owing to these developments, CD4 counts
are increasingly being measured in many RLS at
baseline and for monitoring purposes. However,
viral loads remain largely inaccessible and/or
cost prohibitive – this can lead to the late iden-
tification of virologic failure and development
of resistance. This is particularly problematic
in RLS, where there are often limited treat-
ment options; therefore, the prevention of
resistance remains of the utmost importance.
Unfortunately, several studies in RLS have
shown that changes in CD4 count cannot be
used alone to predictably identify patients with
virologic failure [76–79] . A prospective study
in South Africa investigated the relationship
between CD4 count and virologic failure and
found that a negative CD4 count slope was only
53% sensitive and 64% specific for identifying
patients with virologic failure [76] . A study in
Botswana found that CD4 count increases have
a low predictive value for identifying patients
with suppressed viral loads; an increase in the
absolute CD4 count of more than 50 cells/mm3
after starting HAART was 93% sensitive in
identifying patients who had achieved virologic
suppression but only 62% specific [78] .
Another study by Keiser et al., analyzing out-
comes from 10 antiretroviral treatment programs
in Africa and South America, demonstrated that
the sensitivity of the WHO criteria for immuno-
logic failure in detecting virologic failure among
patients on HAART was only 12.6–17.1% in
these settings, although it was approximately
97% specific [80] . This raises concerns as pre-
sumably the use of immunologic monitoring
without concurrent viral-load monitoring would
lead to a later detection of treatment failure and
www.futuremedicine.com 33
Review | Hoffman, van Griensven, Colebunders & McKellar
delayed switching to a second-line regimen, thus
facilitating the development of viral resistance.
The converse hazard – premature switching
to a second-line regimen based on immuno-
logic criteria in individuals who actually have
viral suppression – exists as well. A study of a
Namibian population on first-line ART, who
met immunologic or clinical criteria for treat-
ment failure, demonstrated that 79% of patients
actually had a suppressed viral load when viral-
load testing was performed [81] . If the decision
to switch to second-line therapy was based on
clinical and immunologic criteria alone, many
patients would be switched to more expensive
and possibly less well-tolerated second-line
­regimens unnecessarily.
As a result, there has been a considerable inter-
est as to whether medication adherence can be
used in addition to the CD4 count for patient
monitoring. Assessment of medication adher-
ence may add value to the CD4 count in terms
of detecting virologic failure or may even be
a better predictor of virologic failure than the
CD4 count alone. A study by Bisson et al. found
that medication adherence, as measured by phar-
macy refills, was independently associated with
virologic failure, although the median level of
adherence among patients with virologic failure
was greater than 90% [77] .
Although identifying virologic failure early is
important in preventing resistance, it may not
have as much of an effect on clinical outcomes
in the developing world as might be expected.
Resources expended on viral-load monitoring
may be better spent on providing more patients
with HAART. The recently released results from
the Development of Antiretroviral Therapy in
Africa (DART) study in Uganda and Zimbabwe
demonstrated minimal differences in outcomes
between a group of patients on HAART who
were clinically monitored versus those receiv-
ing both laboratory and clinical monitoring
(including CD4 count, complete blood count
and chemistries every 12 weeks, but excluding
viral loads) [82] . Among the clinical monitoring
group, the 5-year survival rate was 87%, com-
pared with 90% in the laboratory and clinical
monitoring. This high 5‑year overall survival is
somewhat encouraging, albeit surprising, as the
study group had advanced disease at the time of
initiation on HAART. The difference in out-
comes only became apparent after the second
year of treatment in the 5 year study, indicating
that clinical monitoring alone may be feasible
during the first 2 years of treatment and that
CD4 counts could be reserved for monitoring
treatment beyond this point. Similarly, a com-
puter simulation model developed by Phillips
et al. showed minimal differences in outcomes
between patients monitored by clinical status
alone and those monitored with viral load and
CD4 count or CD4 count alone [83] .
Future perspective
In the next 5–10 years absolute CD4 counts and
CD4 percentages will most likely remain the cor-
nerstone for initiating and monitoring patients
on therapy. Other markers, such as T‑cell sub-
sets as well as activation, inflammatory and/or
coagulation biomarkers, may become increas-
ingly important for evaluating disease progres-
sion, although their anticipated cost for RLS will
pose a formidable challenge. Serious non-AIDS-
related diseases, such as liver, cardiovascular, renal
and non-AIDS malignancies will contribute to
the majority of morbidity and mortality among

Executive summary
CD4 count as a predictor in patient outcome
„„ The baseline CD4 count is a significant predictor for HIV disease progression, survival and treatment outcome.

„„ Individuals with higher baseline CD4 counts at HAART initiation have the best chance for full immune reconstitution.

„„ Patients with lower absolute CD4 counts and percentages at baseline have a higher risk of developing immune reconstitution

inflammatory syndrome.
„„ Patients with lower CD4 counts are at risk for both AIDS- and non-AIDS-related events.

Absolute CD4 count versus CD4 percentage

„„ Absolute CD4 counts may fluctuate among individuals or be influenced by factors including illness and/or medications.

„„ CD4 percentages can provide additional information regarding prognosis in individuals with CD4 counts above 200 cells/mm3.

Discordant CD4 & viral-load response to HAART

„„ Individuals with discordant responses (immunological-only or virological-only responders) do worse than individuals with complete

response, but better than individuals with no response.

CD4 counts in resource-limited settings
„„ CD4 counts are becoming cheaper to obtain and more readily available.

„„ In resource-limited settings clinical monitoring alone may be an option for the first 2 years of treatment.

34 HIV Ther. (2010) 4(1) future science group


HIV-infected patients who are stable on HAART.
Higher CD4 counts have already been shown to
reduce these rates. As antiretroviral treatment
continues to improve with fewer side effects and
less frequent dosing, the CD4 count threshold for
starting therapy is likely to increase. With recent
data supporting the cost–effectiveness of starting
therapy earlier in South Africa [84] , future guide-
lines on starting antiretroviral therapy at higher
CD4 counts should include RLS.
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The authors have no relevant affiliations or financial
involvement with any organization or entity with a finan-
cial interest in or financial conflict with the subject matter
or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or
options, expert testimony, grants or patents received or
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Review | Hoffman, van Griensven, Colebunders & McKellar

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CME@medscape.net. For technical assist-
ance, contact CME@webmd.net. American
Medical Association’s Physician’s Recognition
Award (AMA PRA) credits are accepted in the
US as evidence of participation in CME activi-
ties. For further information on this award,
please refer to http://www.ama-assn.org/ama/
pub/category/2922.html. The AMA has deter-
mined that physicians not licensed in the US
who participate in this CME activity are eli-
gible for AMA PRA Category 1 Credits™.
Through agreements that the AMA has made
with agencies in some countries, AMA PRA
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in the US and want to obtain an AMA PRA
CME credit, please complete the questions
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Activity evaluation: where 1 is strongly disagree and 5 is strongly agree.

1 2 3 4 5

The activity supported the learning objectives.

The material was organized clearly for learning to occur.
The content learned from this activity will impact my practice.
The activity was presented objectively and free of commercial bias.

1. All of the following are advantages of using CD4 counts to help manage patients
with HIV infection, except:
£ A CD4 count is the strongest predictor of disease progression
£ B CD4 count is the strongest predictor of disease survival
£ C Flow cytometry to measure CD4 counts requires little expense or expertise
£ D CD4 counts are relatively objective and simple to follow

2. Which of the following statements about the measurement of CD4 counts among
patients receiving HAART is most accurate?
£ A An adequate CD4 response to treatment is an annual improvement of at least 25 cells/µl
£ B CD4 counts should be checked at least every 6 months upon the initiation of treatment
£ C Changes in the CD4 count of 30% are considered to be clinically significant
£ D Significant physical stress promotes a significant temporary spike in CD4 cell levels

38 HIV Ther. (2010) 4(1) future science group

 Role of the CD4 count in HIV management | Review
3. Which of the following statements about the relationship between CD4 counts and
other means to measure the progress of HIV infection is most accurate?
£ A The CD4 percentage is most useful when the CD4 count is less than 150 cells/µl
£ B The total lymphocyte count correlates best with the CD4 count in children
£ C The CD4 count reliably predicts virologic failure
£ D There is evidence from resource-limited settings that clinical monitoring without CD4
monitoring may be sufficient during the first 2 years of treatment

4. Which of the following statements about CD4 counts and clinical outcomes of HIV
infection is most accurate?
£ A Patients with immunologic-only response have similar clinical outcomes compared with
patients with immunologic plus virologic response
£ B Older adults are more likely to have immunologic-only response
£ C Patients with a higher baseline CD4 count are more likely to have immunologic-only
response
£ D A lower CD4 count predicts a higher risk for immune reconstitution inflammatory
syndrome after the initiation of HAART

future science group www.futuremedicine.com 39