REVIEW

CURRENT
OPINION The evolving role of CD4 cell counts in HIV care
Nathan Ford a, Graeme Meintjes b,c, Marco Vitoria a,
Greg Greene d, and Tom Chiller d

Purpose of review
The role of the CD4 cell count in the management of people living with HIV is once again changing, most
notably with a shift away from using CD4 assays to decide when to start antiretroviral therapy (ART). This
article reflects on the past, current and future role of CD4 cell count testing in HIV programmes, and the
implications for clinicians, programme managers and diagnostics manufacturers.
Recent findings
Following the results of recent randomized trials demonstrating the clinical and public health benefits of
starting ART as soon as possible after HIV diagnosis is confirmed, CD4 cell count is no longer
recommended as a way to decide when to initiate ART. For patients stable on ART, CD4 cell counts are no
longer needed to monitor the response to treatment where HIV viral load testing is available. Nevertheless
CD4 remains the best measurement of a patient’s immune and clinical status, the risk of opportunistic
infections, and supports diagnostic decision-making, particularly for patients with advanced HIV disease.
Summary
As countries revise guidelines to provide ART to all people living with HIV and continue to scale up access
to viral load, strategic choices will need to be made regarding future investments in CD4 cell count and the
appropriate use for clinical disease management.
Keywords
advanced HIV disease, antiretroviral therapy, CD4 cell count, treatment monitoring, viral load

INTRODUCTION The role of the CD4 cell count in the care of

The CD4 cell count has been an essential com-
ponent of HIV treatment and care programmes since
HIV was identified as a disease compromising the
immune system. For healthcare providers, the CD4
cell count has guided key clinical decisions ranging
from when to start antiretroviral therapy (ART) [1 ]
&&
to whether or not to screen for or provide prophy-
laxis against opportunistic infections [2,3]. CD4
testing has also provided valuable insight into pro-
gramme performance over time [4,5] and predicted
patient prognoses, with epidemiologists having
identified associations between CD4 cell counts
and a risk of death [6], life expectancy [7] and treat-
&
ment adherence [8 ]. As a critical test for ART pro-
grammes, deployment of point-of-care (POC) CD4
test devices has been used as a way to improve
linkage to care and accelerate treatment initiation
[9]. Most importantly though, CD4 cell count pro-
vides the best direct measurement of a patient’s
immune status and risk for opportunistic infections,
and it remains an important test with regard to
diagnostic decision-making, particularly for patients
with advanced HIV disease.
persons with HIV/AIDS has evolved over the last 30
years. It began as and remains the best way to
quantify the degree of immunosuppression and
associated risk of AIDS illnesses. However, it is likely
best known for its role in guiding the initiation of
ART in national treatment programs. The roots of
using CD4 thresholds for ART initiation lie in the
early days of the ART era when drug toxicity, afford-
ability, and accessibility of paramount concern.
CD4 subsequently developed into a measure for
a
Department of HIV and Global Hepatitis Programme, World Health
Organization, Geneva, Switzerland, bDivision of Infectious Diseases
and HIV Medicine, Department of Medicine, cClinical Infectious Diseases
Research Initiative, Institute of Infectious Disease and Molecular Medi-
cine, Faculty of Health Sciences, University of Cape Town, Cape Town,
South Africa and dMycotic Diseases Branch, Centers for Disease Con-
trol and Prevention, Atlanta, Georgia, USA
Correspondence to Nathan Ford, PhD, FRCPE, Department of HIV and
Global Hepatitis Programme, World Health Organization, 20 Avenue
Appia, 1211 Geneva 27, Switzerland. Tel: +41 22 791 19 49; fax: +41 22
791 21 11; e-mail: fordn@who.int
Curr Opin HIV AIDS 2017, 12:123–128
DOI:10.1097/COH.0000000000000348

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Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

HIV and diagnostics
KEY POINTS
 The role of the CD4 cell count in HIV management is
changing, with a shift away from using CD4 to decide
when to start ART or monitor treatment efficacy.
 Nevertheless, CD4 remains the best measurement of a
patient’s immune and clinical status, the risk of
opportunistic infections and diagnostic decision-making,
particularly for patients with advanced HIV disease.
 Strategic choices will need to be made regarding future
investments in CD4 cell count and the appropriate use
for clinical disease management.
when it was worth the risks and expense to initiate
ART and was also used to prioritize treatment to
those with more advanced disease in settings where
resources were scarce. The role is again changing
&
[10 ], most notably with a shift away from using
CD4 to decide when to start ART. Recent random-
ized trials have shown that ART should be started in
all HIV-infected patients, irrespective of CD4 cell
&& &&
count [11 ,12 ], Responding to this evidence,
WHO guidelines have been revised to recommend
starting ART as soon as possible following a con-
firmed diagnosis of HIV infection [13], and many
countries are in the process of revising their national
guidelines to reflect this shift in policy [14]. WHO
has also recommended a shift to HIV viral load
instead of CD4 cell count for monitoring ART
[13], though WHO continues to emphasize CD4 cell
count’s important role in evaluating disease status at
baseline and prioritizing appropriate care for
patients found to have progressed to advanced
stages of HIV [10 ].
&
This article reflects on the past, current and
future role of CD4 cell count testing in HIV pro-
grammes, and what this could mean for clinicians,
programme managers and the diagnostics industry.
THE EVOLVING ROLE OF CD4 CELL COUNT
TESTING
When to start treatment
Over the last 30 years, clinicians, researchers and
policy makers have debated the ideal CD4 threshold
for starting ART. During the late 1990s, treatment
was expensive and associated with significant drug
toxicity. Most drug combinations were less robust,
carrying a higher risk of causing drug resistance,
there were fewer treatment options and the decision
about when to start treatment needed to balance
benefits against the significant risks. The prevailing
view during this period was that rates of disease
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progression and death were low at a CD4 cell count
greater than 200 cells/mm3 [6], and any drug
exposure above this threshold could result in severe
and unnecessary side-effects or development of drug
resistance at a time when alternative treatment
&&
options were limited [1 ].
As treatment became more affordable and less
toxic, evidence supporting the overall benefits of
starting treatment at higher CD4 thresholds accu-
mulated, and the threshold for starting treatment
was progressively raised in guidelines. This evol-
ution is reflected in the WHO guidelines over this
period, during which the recommended CD4 cell
count threshold for when to start ART rose from
200 cells/mm3 in 2002 to 350 cells/mm3 in 2010 and
again to 500 cells/mm3 in 2013 [15]. In 2015, just
prior to the WHO Guideline Development Group
meeting for revision of global guidelines, two large
randomized trials were completed and results from
both studies showed that, in terms of reduced mor-
bidity and mortality as a combined endpoint, the
benefit of starting ART at CD4 cell counts above 500
&& &&
outweighed the risks [11 ,12 ]. In light of these
trials, together with evidence that early ART with
virologic suppression reduces the risk of HIV trans-
mission [16], WHO subsequently updated their
guidelines in September of the same year to strongly
recommend that all HIV-positive individuals should
start ART irrespective of CD4 cell count [17].
Although the implementation of this recom-
mendation remains challenging in many resource-
limited settings, the evidence supporting starting
ART at any CD4 cell count is strong, and countries
are moving to revise their national guidelines in line
with the evidence and WHO recommendation [14].
In settings where access to ART may be limited,
WHO continues to recommend prioritizing those
patients with a CD4 cell count less than 350 cells/
mm3, highlighting that CD4 cell count continues to
be the best predictor of those at highest risk of
disease and death and that these priority patients
stand to gain the most from treatment in the
short term.
How to monitor treatment
In the early days of the HIV epidemic, the develop-
ment of specific CD4þ T-cell antibodies paired with
the increasing availability of flow cytometry tech-
nology in a variety of formats and platforms made
CD4 cell counting and thus monitoring of a
patient’s condition during treatment possible for
the first time. However, there has been considerable
debate around the role of such laboratory monitor-
ing in HIV treatment programmes over the past
decade. Initially, there was concern that, without
Volume 12  Number 2  March 2017

the capacity to undertake laboratory monitoring,
low-income countries with a high burden of HIV
may be reluctant to offer ART. In response, the first
WHO guidelines for ART provision issued in 2002
stated that lack of laboratory testing should not be a
barrier to ART [15]. From 2003 onward, WHO guide-
lines stated that CD4 cell count testing was advis-
able, but noted that access remained a barrier and
that initiation of ART remained the priority.
Viral load monitoring of ART was first described
in 1991 [18] and has been recommended by WHO
since 2006 as a more direct measure of response to
treatment, although initially the use was limited to
tertiary centers because of cost and technical con-
straints [15,19]. The cost–effectiveness of viral load
monitoring has been debated. Some studies con-
ducted in Cameroon [20] and Uganda [21] found
that viral load monitoring was not cost-effective
when compared with alternative strategies of
clinical and immunological monitoring. However,
other studies that assessed viral load to confirm
failure in Côte d’Ivoire [22], or to use viral load
instead of CD4 cell count in South Africa [23], found
viral load to be cost effective. WHO and national
guidelines have evolved toward recommending
viral load as the preferred way to monitor treatment
efficacy because of the poor accuracy of CD4
monitoring in predicting viral suppression [24],
and concern that delays in switching ART among
people failing treatment could lead to an accumu-
lation of drug resistance and increased risk of
mortality and morbidity [25]. The latest WHO
guidelines recommend that, where viral load
monitoring is available and patients are stable on
ART, CD4 monitoring can be stopped. This is in
recognition of the fact that CD4 cell count offers
little added information in patients who are clin-
ically well and virologically suppressed on ART
&&
[26 ], and that the cost of scaling up viral load
can be partially offset by limiting CD4 testing to a
single baseline or several early tests, where it is still
necessary to assess the patient’s clinical status before
safely initiating ART [23].
Informing treatment choices
Until 2013, nevirapine was among the most widely
used antiretroviral drugs, and was recommended by
WHO as part of first-line ART. However, nevirapine
use has been associated with a heightened risk of
hepatic and cutaneous adverse drug reactions
particularly in women at higher CD4 cell counts,
leading to recommendations against using nevira-
pine in women with CD4 cell counts more than
250 cells/mm3 and in men with CD4 cell counts
more than 400 cells/mm3; this concern further
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The evolving role of CD4 cell counts in HIV care Ford et al.
complicated clinical management [27]. In 2013,
WHO gave preference to efavirenz over nevirapine
in first-line ART [13], and there has been a rapid shift
away from nevirapine use by countries [14]. New
drug options such as dolutegravir are even better
tolerated, removing any prospect that CD4 cell
count determination will be needed in the future
to guide antiretroviral drug choice.
Availability of tests
Recent survey findings indicate that global capacity
of available CD4 instruments is sufficient to meet
the needs of all people living with HIV/AIDS, irre-
spective of treatment status [28]. However, CD4
instruments are considerably underutilized, with
only 13.7% of existing CD4 capacity utilized in
2013 across 50 countries reporting data. Key reasons
for nonutilization included noninstallation, break-
down for CD4 conventional instruments with lim-
ited or no maintenance contracts and lack of
reagents for POC CD4 instruments [28].
In contrast, viral load instrument capacity is not
adequate to meet the needs of all people living with
HIV/AIDS. In 2013, 28% of reporting countries did
not have adequate viral load (VL) capacity to per-
form at least one VL test per patient/year on ART. In
addition, only 37% of theoretical instrument test
capacity was actually being used, mainly because of
noninstallation and lack of reagents [28]. Many
countries continue to rely substantially on donor
funding to deliver viral load, which raises concerns
about long-term sustainability.
As viral load continues to be scaled up, countries
will need to make strategic decisions regarding
relative investments in scale-up and placement of
CD4 and viral load technologies.
FUTURE ROLE OF CD4 CELL COUNT
TESTING
WHO guidelines no longer recommend CD4 for ART
initiation or disease monitoring, though baseline
CD4 is still recommended and plays a vital role
in guiding clinical management of patients with
advanced disease, a group that still makes up nearly
half of all people living with HIV starting/restarting
treatment [7]. WHO guidelines recommend that
ART can be started irrespective of CD4 cell count
and that CD4 cell count monitoring can be stopped
in patients who are stable on ART and that ART
efficacy can thereafter be monitored with viral load.
These two recommendations in particular are likely
to result in fewer CD4 cell counts needed and thus
fewer resources necessary to commit to CD4 testing
in HIV programmes. For example, in Namibia,
www.co-hivandaids.com 125
HIV and diagnostics
Table 1. Past and future role of CD4 cell count testing
Role of CD4 testing in PLHIV Past
Starting and stopping cotrimoxazole Yes
prophylaxis
Cryptococcal antigen testing Yes
TB diagnosis (urine LAM) No
ART initiation Yes
ART monitoring Yes
ART drug choice (use of nevirapine) Yes
ART, antiretroviral therapy; LAM, lipoarabinomannan; PLHIV, people living
with HIV; TB, tuberculosis.
changing from CD4 to viral load monitoring and
using CD4 only as a baseline test have resulted in
nearly a 90% decrease in CD4 cell counts being
performed, which has helped to offset the increase
in costs for more viral load monitoring. Neverthe-
less, CD4 cell count testing still has an important
role to play as a way to assess clinical status of a
patient at first initiation of treatment, most notably
in the management of advanced HIV disease (Table
1). CD4 cell count will also be important in evaluat-
ing patients who are failing ART and who come in
after being off treatment for some time.
Management of advanced disease
CD4 cell count testing is one of the most important
tools for assisting clinical management decisions in
patients with advanced disease. In particular, a CD4
cell count less than 200 cells/mm3 is considered a
critical threshold for heightened risk of death [6,29]
and is used as the current WHO definition of
advanced HIV disease [30]. Screening for cryptococ-
cal antigen (CrAg) is recommended for all patients
with a CD4 cell count less than 100 cells/mm3[13],
and several randomized trials have found a positive
benefit associated with a package of interventions
aimed at reducing mortality among patients pre-
senting below this CD4 cell count threshold
[31,32]. WHO also recommends the use of the urine
lateral flow-LAM assay to assist in the diagnosis of TB
in a specific category of HIV-positive individuals
presenting with CD4 less than 100 cells/mm3; this
threshold was chosen because of reduced diagnostic
accuracy (in particular poor sensitivity) at higher
CD4 cell counts [13,33]. Cotrimoxazole is a fixed-
dose combination of two antimicrobial drugs (sul-
famethoxazole and trimethoprim) that prevents
morbidity and mortality from a variety of bacterial,
fungal and protozoan infections. Provision of cotri-
moxazole prophylaxis has been recommended
by WHO since 2006. The latest guidelines, issued
in 2014, recommend giving cotrimoxazole
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prophylaxis to all HIV-infected adults with a CD4
cell count less than 350 cells/mm3, and discontinu-
Current ing once patients are stable on ART [2]. In settings
Yes where malaria and/or severe bacterial infections are
highly prevalent, cotrimoxazole prophylaxis should
Yes be initiated and continued regardless of CD4 cell
Yes count; cotrimoxazole prophylaxis should also be
No administered to all HIV-infected people with active
No
TB disease regardless of CD4 cell counts.
Although the notion that advanced disease will
No
cease to pose a problem as ART programmes expand,
trends in CD4 cell counts over the past decade
indicate the advanced disease is and will for the
foreseeable future remain an issue for HIV pro-
grammes. The average CD4 cell count at start of
ART has somewhat risen globally over the last decade,
reflecting the evolution in treatment guidelines
toward recommending starting treatment at higher
CD4 cell counts [4,34]. However, the proportion of
patients presenting with advanced HIV disease has
remained relatively constant, with a 2015 meta-
analysis of CD4 trends estimating that over half of
patients have progressed to advanced disease by the
time of ART initiation [4,35,36]. Tuberculosis, bac-
terial infections, fungal infections and other AIDS-
related infections continue to be leading causes of
hospitalization and mortality among people living
with HIV globally [37]. Although this persistence of
advanced HIV disease partly reflects the fact that
people continue to be diagnosed late in their HIV
infection – almost one-third of HIV-positive patients
admitted to hospital are diagnosed at the time of
admission [37] – an important proportion of patients
presenting with advanced disease is also represented
by HIV-positive individuals who have already started
ART but subsequently interrupted their treatment
[38,39]. Persons with HIV/AIDS who are defaulting
on therapy represent an ever increasing number of
patients seen in clinics and admitted to hospital [38],
with defaulters constituting over half of late present-
ing patients (CD4 < 350 cells/ml) in some settings
[40]. These challenges will be critical to address mov-
ing forward in the test and treat era.
For these reasons, WHO recommends that HIV
programmes should retain the capacity to perform
CD4 cell count at baseline and during the case of
treatment failure, as this remains one of the best
predictors of general patient wellness, disease pro-
gression and mortality risk, and can guide further
diagnostic tests to address the causes of these
mortality concerns [13].
Future research in CD4 testing
Much has been learned about CD4 testing over the
past three decades and a couple of the major
Volume 12  Number 2  March 2017

concerns remain to be addressed in the near future.
One major concern is the potential for delay in
treatment initiation that could result from CD4
turnaround times and another is the cost of con-
tinuing to support a CD4 infrastructure based on
flow cytometry, especially as the bulk of testing
moves to viral load. More affordable and user-
friendly POC testing platforms have offered a viable
alternative, although issues remain with quality
assurance, testing volumes maintenance and supply
chain management. Considerable progress has been
made in the development of even more robust,
simpler, faster and more affordable testing plat-
forms, such as highly accurate microchip assays
and semiquantitative lateral flow assays (LFAs) that
would indicate whether or not a patient was above
or below a certain CD4 cell count. Although much
of this work has fallen to the wayside in the wake of
WHO guidance to treat regardless of CD4 cell count,
this technology remains relevant in identifying
patients with advanced disease and continued effort
and investment remains important. Ideally, a simple
semiquantitative CD4 LFA would provide a cheap
and sustainable alternative to current CD4 testing in
the future. Such a test could be performed during a
patient’s initial visit without the need to collect and
send off specimens, and would allow clinicians to
determine if a patient has advanced disease (CD4 <
200 cells/mm3) and needs additional screening and
treatment/prophylaxis of opportunistic infections
necessary to safely initiate ART. Microchip technol-
ogy, while slightly more costly, has the added
benefit of multiplexing, allowing the consolidation
of CD4 with other tests, such as CrAg and syphilis. A
recent collaboration between UNICEF and South
Africa’s Rhodes University is working on offering
another alternative for rapid CD4 testing, using a
colorimetric aptamer-based test strip and a reader
that attaches to a cell phone camera to produce an
accurate quantitative CD4 result in less than 20 min.
Such innovation will be crucial to CD4 testing in the
future. The development of better POC testing plat-
forms should be strongly encouraged and not aban-
doned because of the elimination of CD4 thresholds
for treatment initiation.
Another area of future research will be to explore
the role of CD4 cell count monitoring as a tool to
assist clinical decisions in current and future treat-
ment strategies beyond the management of
advanced HIV disease. Several new experimental
HIV cure strategies and structured treatment inter-
ruption protocols are using high CD4 thresholds as a
criterion to start/stop therapy [41,42]. There are
several safety and ethical concerns about this
approach that remain to be clarified [43]. A recent
study suggested that CD4/CD8 ratio and its
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The evolving role of CD4 cell counts in HIV care Ford et al.
variation over time can be independent predictors
of cardiovascular disease (CVD) events in HIV-
infected individuals [44]. Further studies to examine
its role as clinical biomarker of CVD outcomes and
immune senescence are needed in prospective stud-
ies and larger cohorts. Finally, the use of CD4 cell
count reference curves to identify immune nonres-
ponse among virally suppressed patients can be an
additional tool for clinicians when evaluating
response to ART [45].
Specifications for an ideal CD4 test
As we move into the era of test and treat, CD4 count
testing will be a critical component of clinical assess-
ment at baseline initiation of ART and to evaluate
immune status after ART interruptions and noncom-
pliance. An ideal test would only need to be semi-
quantitative with cutoffs at either 100 or 200 cells
mm3, or possibly both, and in a rapid diagnostic test
or POC format. This would ensure that testing could
be done easily and quickly during initiation of ART at
baseline and in treatment failure situations, where
clinical status of the patient is a key to assess.
CONCLUSION
CD4 cell count testing has made a critical contri-
bution to the management of people living with
HIV over the past three decades. Increased access to
ART and viral load, and recent policy changes rec-
ommending ART start in all HIV-positive individ-
uals irrespective of immune status have brought
into question the future role of CD4 cell count
testing in the global HIV response. In light of this,
the role of CD4 testing is likely to become more
restricted to baseline testing, returning to its original
purpose as an essential tool in the assessment of
disease progression in patients and, most impor-
tantly, in the proper management of patients with
advanced HIV disease. As viral load continues to be
scaled up, countries will need to make strategic
decisions regarding relative investments in further
scale up of CD4 and viral load technologies. We
encourage test manufacturers to pursue CD4 tech-
nologies that will allow this important test to con-
tinue to be accessible in resource-limited settings as
this shift occurs.
Acknowledgements
None.
Disclaimer: The contents of this publication are solely the
responsibility of the authors and do not necessarily
represent the official views of the Centers for Disease
Control and Prevention or the World Health Organization.
www.co-hivandaids.com 127
HIV and diagnostics
Financial support and sponsorship
There is no financial support related to this work.
Conflicts of interest
None of the authors have any conflicts of interest.
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Volume 12  Number 2  March 2017