The role of CD4 count and viral load tests in monitoring HIV positive Patients

Abstract

Viral load Measurement is the mainstay to
indentify viral replication. Estimating viral load is the best in
discriminating between treatment failure, non-adherence, and can
serve as a proxy for the risk of transmission of the HIV virus at
the population level. In the absence of viral load testing,
immunological monitoring is considered to indicate treatment
failure, although falls in CD4 count correlate poorly with
virological failure. However, in the absence of viral load and
CD4 tests, syndromic management of human immunodeficiency virus
could be used to indicate the need for treatment switching.
Medical doctors are advised to desist in applying syndromic
management of HIV where, CD4 count is possible, laboratory values
of CD4 count must be obtained before certain treatment option is
indicated. The HIV resistance testing is not always practicable
in developing countries due to lack of second or third choice
therapy and due to economic reasons.

Keywords: HIV, CD4 count, Viral
load.

Introduction

The Virus causing AIDS was first isolated
in 1983 by Dr. Montagnier of France, and, later, in 1984 by Gallo
and Levy of the United States of America. However, the name of
the virus (Human Immunodeficiency Virus) was given at the
international conference in 1986. The virus isolated in West
Africa was termed HIV-2, and HIV- 1 was given to the former. HIV
is categorized to the rentivirus, subfamily of the retrovirus,
and a mature virus has a D- type particle with a diameter of
110nm. It is an RNA virus, has capsid around the core and an
envelope outside the capsid. HIV penetrates into cells by binding
of the envelope"s gp120 with CD4 antigen on the surface of the
helper T- lymphocytes. The viral RNA is transformed to DNA by
reverse transcription, done by enzymatic reactions and integrated
to chromosomal DNA of helper T lymphocytes. Genomic DNA of HIV
contains nine genes mostly gag, pol, env, tat, rev, nef, vif vpu
and vpr between both ends. HIV attacks CD4 helper cells as a
target and destroys it.

HIV remains one of the leading causes of
infectious disease worldwide. It is devastating in terms of
costs, death, human suffering, lowering of life expectancy by
decades, children orphan and loss of income. The World Health
Organization data (2013), showed that 35 million people are
currently living with HIV. The number of people newly infected
with HIV in 2013 was a total of 2.1 million people, out of these,
adults was 1.9 million, while children was 240,000. The death
burden of AIDS in 2013 was 1.5 million, and adults was 1.3
million, while 190,000 were children ages about 15 years on
average. The HIV/AIDS pandemic crisis is far from over and policy
makers and various governmental agencies should make policies on
strategic means for more funding, preventive measures, Laboratory
testing, and treatment program. In 2013, about 2 million people
newly enrolled for antiretroviral treatment, this is the largest
ever annual increase. The percentage of children in need of
treatment in 2013 was 23 % compared to adults of about 37%.
However, 67% of pregnant women living with HIV received treatment
in 2013 to prevent vertical transmission. Dr. Richard Feachem on
Rice University speech in 2003 said, "Most of what we once
thought we knew about global health, has been proved wrong by the
relentless advances of HIV/AIDS, tuberculosis, and
Malaria…….there can be no more urgent cause facing
us today. In Africa, the enemy is already among us, In Asia; the
enemy is at the gates. “

Role of CD4 count
and Viral load in monitoring HIV pandemic

Proper laboratory based diagnostics for
screening, diagnosis, treatment initiation, and the monitoring of
treatment efficacy are critical in managing the disease and
reducing the number of new infections each year. The goal of
providing Antiretroviral therapy (ART) is to suppress HIV to
undetectable levels for life. Viral suppression therefore,
reduces illness, death, the development of drug resistance, and
the spread of new infections. When HIV is undetectable, it means
that the virus is not replicating, and people can live healthy
and productive life.

However, to determine when treatment should
be started and whether treatment is working, two most important
diagnostic tests are CD4 count (absolute and percentage), which
measures the strength of the body´s immunological response,
and HIV viral load test, which measures the amount of viral
replication in the blood. These tests must be carried out by
qualified Medical laboratory scientist, and effective treatment
procedure results in a very low (undetectable) viral load and CD4
count within the normal range.

CD4 testing is a form of immunological
monitoring and is mostly effectively used in deciding whether and
when to start HIV treatment. CD4 count in developing countries
today is mainly laboratory based and due to shortage of qualified
medical laboratory scientists, results are delayed due to
excessive work load, and this leads to delay in making
appropriate treatment decisions by the Physician. The adoption of
Point- of – care (POC) CD4 testing has accelerated
treatment initiation and reduces the number of patients lost to
follow up while test results are awaited.

Viral load monitoring is the optimal tool
to determine if treatment is working and has long been the
standard of care for treatment monitoring in developed countries.
HIV treatment once started, must be taken for the rest of life,
and routine treatment monitoring is necessary to ensure that a
person`s ART regime continues to be effective. If the treatment
stops working, the patient becomes sick and the risk of drug
resistance and transmission is increased. The first indicator
that a patient is no longer under optimal care is a detectable
viral load – thus, the best and earliest indicator that a
clinical intervention is needed is the viral load
measurement.

Point – of – care (POC) testing
apparatus refers to medical testing at or near the point of care,
conducted within a very short time, for example, 10 to 30 minutes
of sample collection, and followed by an immediate medical
decision based on the results. POC testing eliminates delay
associated with waiting for the laboratory based test results.
POC diagnostics support early treatment and rapid initiation.
However, depending on the context and the number of patients, POC
may not be appropriate for every setting. Furthermore, POC
testing must be monitored by the medical Laboratory scientist and
must obey testing site neutrality. What then, is this testing
site neutrality? This means that, it does not matter where the
diagnostic test is performed or who performs the test, whether
medically trained or not: all testing sites must follow the same
regulatory requirements based on the complexity of the test. The
complexity of implementing viral load technology in developing
countries as well as higher upfront costs compared to other
diagnostic technologies, has so far hindered adoption in
developing countries and high HIV prevalence settings, where
access to optimal treatment monitoring remains dismally
low.

CD4 testing is recommended to measure
immunological function after initiating ART, to confirm that CD4
cells have reconstituted and remain in an acceptable range
(always above 500 cells/&µl, but definitely above 200
cells/&µl), a normal CD4 count ranges from 500 to 1000
cells/mm3. A CD4 count fewer than 200 cells/mm3 is one of the
qualifications for AIDS diagnosis. CD4 cell count is not
particularly effective for long time treatment monitoring. CD4
count cannot detect early signs of adherence problem or treatment
failure because CD4 count naturally fluctuates a great deal and
measuring CD4 count cannot detect the source of the problem
– increasing viraemia. The absolute CD4 count is a
calculated value based on the total of white blood cell count and
the percentages of total and CD4+ T- lymphocytes. Thus absolute
number may fluctuate in individuals or may be influenced by
factors that may affect the total WBC and lymphocyte percentages,
such as use of bone marrow suppressive medications or presence of
acute infections. Splenectomy or co-infection with human T
lymphocyte virus type1 may cause misleading elevated CD4 counts.
Alpha-interferon also may reduce the absolute CD4 count without
changing the CD4 percentage. In all these cases, CD4 percentages
remain stable and may be a more appropriate parameter to assess a
patient"s immune function. Treatment efficacy should result in an
undetectable viral load within six to twelve months after ART
treatment initiation; a detectable viral load after this period
shows that treatment is not effective and could be falling. CD4
testing do not offer timely enough information to initiate an
optimized treatment response, therefore, the eleven country MONET
clinical trials on treatment simplification reported that if
treatment was effective and viral load was suppressed, CD4
monitoring offered no added value. The recent research work of
Gale et al 2013 reported that patients with CD4 count = 300
cells/&µl had almost 97% probability of retaining
durable CD4 count =200 cells/&µl for four years, if
their viral load stayed below 200 copies/ml, and this was
increased to 99% if non- HIV causes of CD4 cell drop was
excluded.

Viral load monitoring coupled with enhanced
adherence support, helps deliver improved health outcomes both
for the individual patients by reducing morbidity and mortality,
and for the particular communities by reducing transmission of
the HIV virus from one person to another. Viral load is
fundamental for treatment initiation with patients initiating
treatment at very high viral loads (=100,000 copies/ml) despite
having high CD4 counts. Why? This is because ongoing HIV
replication is very harmful. However, viral load testing is the
standard of care in wealthy nations, routing virological
monitoring is a mirage or sparsely available in poorly depressed
economic nations, owing to costs, complexity, and scarcity of
trained medical laboratory scientists. The highest measure of
viral load can be over 500,000 copies/ml while the lowest levels
of detectable viral load can be 40 to 75 copies/ml. Low viral
load means lower amount of HIV activity. The primary goal of ART
is to lower the viral load to levels below 40 to 75 copies/ml. It
is pertinent to note that just because viral load may fall below
these levels, does not represent that HIV is gone from the
body.

Viral load testing remains undisputedly a
gold standard for treatment monitoring in various
ways:

• Ensures treatment efficacy: It detects
  adherence problems early, often before drug resistance
  develops. It prolongs the use of more affordable, well
  tolerated one – pill – a – day first line
  drug.

• Supports treatment adherence: Viral
  load triggers need for intensive adherence counseling that
  can result in viral re-suppression and contributes to
  treatment literacy and motivation to reach and maintain an
  undetectable viral load. Once non adherence has been
  addressed, enables early and specific confirmation of
  treatment failure due to drug resistance mutations.
  Virological testing enables time switching to a more
  effective drug regime, before drug resistance mutations
  accumulate and reduce the efficacy of second and third line
  regimes. It identifies risks of vertical transmission during
  pregnancy, breast feeding and between sexual
  partners.

• Identifies early risk of treatment
  failure: Viral load testing prevents unnecessary switches,
  based on non-specific immunological monitoring, to more
  expensive second line drugs.

The world Health Organization in 2013
recommended that antiretroviral therapy be started at once,
regardless of CD4 count for seropositive patients that are
pregnant, breast feeding, active tuberculosis, and severe
hepatitis B virus, HIV positive in a serodiscordant relationship
and in children under 5 years of age. In adults and adolescents,
however, a CD4 count of 350 cells/mm3 was an indicator for urgent
treatment in 2010, but, in 2013, this was extended to include
patients with CD4 count of 500 Cells/mm3.There are a number of
factors to consider when taken decisions on what antiretroviral
combination to give to patients. The first combination of drugs
that a patient takes is called first line therapy. Furthermore,
an effective HIV therapy for seropositive patients should have a
combination of three drugs, which are divided into five different
classes. The World Health Organization advised in 2013, that an
antiretroviral combination that consists of two drugs from
Nucleoside/Nucleotide Reverse Transcriptase inhibitor class and
another drug from the Non-Nucleoside Reverse Transcriptase
inhibitor class be taken.

In developing nations, facilities to
measure viral load and CD4 count are mainly unavailable, in this
case; therefore, medical officers will depend on World Health
Organization clinical staging of HIV disease. These clinical
staging are divided into four stages. HIV diseases based on
clinical symptoms are never accurate, grossly unreliable, and
present errors associated with mis-diagnosis. They are mainly
applicable to adults and adolescents, and are stated
as:

Clinical Stage 1: It consists of
asymptomatic, Persistent generalized lymphadenopathy
etc.

Clinical Stage 2: Here, we have unexplained
weight loss, recurrent respiratory tract infections, Herpes
zoster, Angular chelitis, recurrent oral ulceration, popular
pruritic eruptions, dermatitis, fungal nail infections,
etc.

Clinical Stage 3: In this stage, there are;
severe bacterial infections, pulmonary tuberculosis, Oral hairy
leukoplasia, Persistent oral candidiasis, unexplained anemia,
neutropenia, and or thrombocytopenia, Persistent fever more than
a month, chronic diarrhea more than a month and unexplained
severe weight loss, etc.

Clinical Stage 4: HIV wasting syndrome,
Pneumocytis pneumonia, extra- pulmonary tuberculosis, Kaposi
sarcoma and HIV encephalopathy etc.

Treatment should start as soon as the HIV
positive patient is showing clinical syndromes of stage 3 or
stage 4. These clinical stages are identified typically by the
emergence of opportunistic infections and certain cancers, which
a healthy immune body would normally fight off.

Conclusion

The introduction of efficient diagnostic
equipment for screening and monitoring of HIV positive patients
have revolutionized the HIV pandemic infection. The introduction
of CD4 count, and viral load scientific tests, have reduced
medical errors associated by the use of clinical staging
treatment method, while, antiretroviral therapy has brought
tremendous and sporadic changes in ensuring that HIV positive
patients could live a normal life style. The point- of- care CD4
initiative have made a paradigm shift in improved retention to
care and reduced workload in traditional laboratories and loss to
follow up of these patients. Once again, medical doctors are
advised not to depend on trial and error method of clinical
staging, but, instead, seek laboratory oriented values of viral
load and CD4 count as soon as possible before initiating ART to
all seropositive patients. If viral load testing is provided by
all developing nations, the seropositive patients globally will
enjoy healthy prolonged lives, and the HIV conflict will be
reduced. The better and effective utilization of global fund for
HIV program by various governmental agencies of developing
countries, and adequate pricing of laboratory reagents,
equipment, and re-training of qualified medical laboratory
scientists, there could be a cost effective solution to the
general burden of HIV financial crisis.

References

African society for Laboratory medicine
meeting, May, 2012.

Ambas J et al (2012): The MONET trial: Week
114 analysis of the efficacy of DRV/r monotherapy Vs DRV/r plus
two nucleoside reverse transcriptase inhibitors for patients with
viral load =50 HIV-1 RNA copies /ml. HIV Med
13:398-405.

Bernard NF et al (1998): Effect of
splenectomy on T cell subsets and plasma HIV viral titers in HIV
infected patients. J Hum Virol 1(5): 338-345.

Bertagnollo S et al (2013): The impact of
HIV drug resistance on the selection of first and second line ART
in resource poor setting. J infec Dis, 207: 545-548.

Casseb J et al (2007): T- CD4+ cell count
among patients co-infected with human immunodeficiency virus type
1 (HIV1) and HTLV-1: High prevalence of tropical spastic
paraparesis/HTLV-1 associated myelopathy. Rev. Inst Med Trop. Sao
Paulo, Brazil, 49(4):231-233.

Clavel F et al (1986): Molecular cloning
and polymorphism of the human immunodeficiency virus type 2.
Nature, 324: 692-695.

Department of Health & human services
(2011): Panel on antiretroviral guidelines for adults and
adolescents. Guidelines for the use of antiretroviral agents in
HIV1 infected adults and adolescents, 5:1-166.

Fareyra C et al (2012): Evaluation of
clinical and immunological markers for predicting virological
failure in a HIV/AIDS treatment cohort in Busia, Kenya. PLOS One
7(11): e49834.

Gale H et al (2013): Is frequent CD4+ T
lymphocytes count monitoring necessary for persons with
counts=300 cells /&µl and HIV1 viral suppression? Clin
Infec Dis ePub ahead of print.

Hosselnipour, MC et al (2013): Emergency of
HIV drug resistance during first and second line ART in resource
limited setting. J Infec Dis 207: 549-556.

Lynen L et al (2010): Monitoring for
treatment failure in patients on first line ART in resource
constrained settings. Curr Opin HIV AIDS, 5: 1-5.

Medecins Sans Frontieres (2012):
Undetectable: How viral load monitoring can improve HIV treatment
in developing countries 1-35.

Mugavero MJ et al (2011): Viremia copy
years predict mortality among treatment naïve human
immunodeficiency virus infected patients initiating ART. Clin
infec Dis, 53: 927-935.

Popvic, M et al (1984): Detection,
isolation and continuous production of cytopathic retroviruses
from patients with AIDs and pre-AIDs. Science
224:497-500.

Sax PE (2013): Can we break the habit of
route CD4 monitoring in HIV care .Clin Infec Dis, Epub ahead of
print.

World Health organization (2013):
Consolidated guidelines on the use of antiretroviral drugs for
treating and preventing HIV infection: Recommendations for a
public health approach.

World Health Organization (2013): Data and
statistics.

Autor:

Dr. Peter Ubah Okeke,

Ph.D, AMLSCN

Ministry of Health, Cape Verde