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Clinical Stages of HIV

Article · January 2011

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Shruti Rastogi Shishir Agrahari

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Udai Pratap Singh Ashish Verma

Amity University Uttar Pradesh, NOIDA, India Jadavpur University
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 Invited Contribution

Clinical Stages of HIV

Shruti Rastogi, Shishir Agrahari, Udai Pratap Singh, Anchal Singh1 and Ashish Swarup Verma*
Amity Institute of Biotechnology, Amity University-Uttar Pradesh, Sector-125, Noida (UP)-201 303, India
1 Present address: Department of Microbiology and Immunology, Kirksville College of Osteopathic Medicine,

A.T. Still University of Health Sciences, 800 W Jefferson Street, Kirksville, MO 63501, USA

H
uman Immuno-deficiency Virus (HIV) infection
is preceded by the development of Acquired
Immuno-Deficiency Syndrome (AIDS). AIDS is
the last outcome of HIV infections. AIDS is a fatal and
terminal condition for HIV infected patients. AIDS is a
stage when HIV-seropositive patients are presented with
various AIDS-related complications like opportunistic
infections and cancer.
The first case of HIV infections was reported in 1981
among 5 gay men from Los Angeles, USA. Although
at that time, neither HIV nor AIDS was a part of
medical vocabulary, but these cases were reported
with Pneumocystis carinii pneumonia (PCP). This is a
disease not commonly noticed among general population,
but has been reported with higher incidences among
immune-deficient individuals. Initially, these patients
were diagnosed with this rare disease PCP, which could
be due to their immune-deficient conditions. There was
sudden increase in demand for the drug to treat PCP
which was observed for the first time by drug-technician
Ms. Sandra Ford from Center for Disease Control and
Prevention, Atlanta, USA (CDC). Her observations raised
the alarm to look into this sudden increase of immuno-
deficiency disorders. Soon after the initial cases of PCP,
world community noticed an increase in incidences of
AIDS as disease in all communities, among all age group
and almost from all the corners of world. This kind of
increase in numbers of HIV infections gave a sense of
feeling that this infection is spreading like a wild fire.
The first case was reported by Michael Gottlieb in 1981
in New England Journal of Medicine.
The most unfortunate part of this saga is that there was
no medicine to treat these infections, which led to the
*Address for correspondence:
Dr. Ashish S. Verma
Professor of Biotechnology
Amity Institute of Biotechnology
Amity University-Uttar Pradesh
evolution of various myths. Some of these myths turned
out to increase the spread of HIV infections. Initially, it
was noticed that these infections are associated with a
specific community following a unique lifestyle, which
was not approved by various religious faiths. Therefore,
HIV/AIDS received unexpected attention from all the
quarters, and lots of money was invested to identify the
causative organism as well as a treatment for the same.
Later on, in 1983, Luc Montagnier from Pasteur Institute,
Paris discovered the causative organism for the disease
and named it as Lymph Adenopathy Virus (LAV). His
findings were confirmed by Robert Gallo in 1984; Luc
Montagnier was awarded Nobel Prize for his contribution
and discovery of HIV in 2008. In literature various
names for HIV were found until 1998, when the final
name of this causative organism was adopted as HIV by
international committee for taxonomy of viruses.
In general, we know that HIV is one virus, but in reality,
HIV is of two types, HIV-1 and HIV-2. Out of these
two, HIV-1 is more prevalent and progresses rapidly
with fatal consequences while HIV-2 is slow progressing
and mostly confined to African continent. HIV is mostly
transmitted via body fluid like blood, semen, vaginal
fluid, breast milk, vaginal fluid, etc. The major means
of HIV transmission is due to unprotected sex (vaginal,
oral or anal sex), blood transfusion, contaminated
hypodermic needles, exchange between mother and baby
during pregnancy, child birth and breast feeding. As per
UNAIDS (2009) report, more than 34 million people are
living with HIV infections out of which more than 2
million are children below the age of 16 years. Every
year almost 2 million people get new infections.
HIV infects cells via CD4 receptors, that is the reason
it targets CD4 positive T-cells. For HIV infection, other
co-receptors are also found to be important which are
known as chemokine receptors. Apart from T-cells, HIV
is also known to infect other cells like monocytes. HIV
is a retrovirus, therefore, its genetic information is carried
by RNA rather than DNA. To convert RNA into DNA,
Page – 29

Sector-125, Noida (UP)-201303

India HIV has a unique enzyme known as reverse transcriptase.
Email: asverma@amity.edu HIV attaches to CD4 receptors and finds its entry into
Phone: (120) 4392757 the cells, where RNA is converted into cDNA, which
Biolixir, 2011, Volume 1: 29-31

finally integrates with the host cell’s genome. Integration
of the viral DNA (proviral DNA) to the host cell genome
initiates viral replication leading to production of new
virion particles, which in turn infect new cells. In certain
cells, HIV remains latently infected for a long time, and
may become an active source of viral replication due to
some kind of activation, for which the exact mechanism
is not well known.
Azidothymidine is the first medicine approved by Federal
Drug Administration (FDA), USA to treat HIV infections.
Later on various drugs have been developed for HIV
treatment which blocks different stages of HIV replication.
There is no doubt that there is an unprecedented progress
in anti-retroviral treatments for HIV, which has helped
tremendously to improve the morbidity and mortality
among HIV seropositives. Due to the availability of
improved anti-retroviral drugs, a HIV seropositive can
live more than 20 years post HIV-infections. Out of
all these treatment strategies, a new treatment regimen
i.e., Highly Active Anti-retroviral Treatment (HAART)
is found to be very effective to reduce viral replication
significantly. Still the fact is that HIV infection can be
controlled only and cannot be cured.
Since, HIV infection is usually fatal and HIV infected
patients are found all across the globe, therefore, it was
very difficult to manage and understand the treatment
strategies for HIV infection, therefore, a need for
classification of HIV infection was realized.
Need for Classification: AIDs has emerged as a new
disease with increasing number of victims day-by-day.
With time, various diagnostic tests have been developed
along with various drugs to treat HIV infections.
Combination of drugs and diagnostic tests has helped
to generate data both for clinical situations as well as
in laboratory conditions. Every clinician or groups of
clinicians as well as laboratory scientists were interpreting
data to their best abilities to treat patients. This kind of
prevailing situation was realized as a major impediment
for desired improvement to treat HIV patients. Non-
availability of coherent guidelines became a problem to
monitor HIV surveillance, epidemiology, health status of
patients, designing new diagnostic tools, recommendation
of different diagnostic tests, recommendation of
appropriate treatment strategies, maintenance of clinical
data, consultation and advice from other clinician for
the same patients and for comparison of prevalence
from one geographical location to another. It was felt
Page – 30
that improvement of the prevailing limitations for HIV
infections can be achieved by developing a classification
of clinical conditions into different categories on the
basis of existing clinical and laboratory data.
Biolixir, 2011, Volume 1: 29-31
Rastogi, Agrahari, Singh, Singh and Verma
This task was undertaken by Center for Disease Control
and Prevention, Atlanta, USA (CDC). They have given
the first ever classification of various clinical conditions of
HIV seropositives in 1986, which has helped tremendously
for the clinical management of HIV patients and with
time, CDC keeps on revising this classification based on
better understanding of the clinical conditions as well
as diagnostic data. Later on, World Health Organization
(WHO) also developed a new classification for HIV
infection, which works as a global reference standard.
Although various other classification systems do exist
in the literature, but the most acceptable and followed
ones are classification of clinical conditions developed
either by CDC or WHO. The classification systems
developed by CDC and WHO have the same purpose
and their core and soul is the same, but they cater the
need in different situations.
CDC has developed a classification system initially to
cater the need for a better understanding and developing
strategies to control HIV infection in USA, USA being one
of the most resourceful countries of the world. Therefore,
criteria for classification was based more on diagnostic
data i.e., CD4 counts and viral loads, as we know these
two are closely linked to each other. As matter of fact,
these two clinical parameters are inversely related to each
other. Undoubtedly, CDC system has certain important
end points which are very useful to understand, design
and develop treatment regimen for HIV seropositives.
It is unfortunate that all the people who get HIV
infection do not live in resourceful settings like USA.
These patients neither have all the facility to monitor
the progression of disease with the help of expensive
diagnostic tests nor even do they have access to all the
expensive and effective drugs either to treat or control
HIV infections. As a matter of fact, a due consideration
was given by WHO to rescue these patients, who live
in less fortunate conditions, therefore WHO developed a
classification system in 1990, which is based simply on
the clinical signs and symptoms, although at some point
of time, these cases have to undergo diagnostic tests too
for further confirmation. Some of these situations have
been improved with the development of a new institution
known as UNAIDS, which works under the umbrella of
United Nations (UN).
Staging and Classification System by WHO: The WHO
clinical staging system for HIV/AIDS was developed in
1990 and it has emphasized on clinical parameters as a
guide-line for clinical decision-making. The WHO system
is very useful and has been widely used in resource
limited settings, where patients have access to limited
laboratory services, particularly the African Region. This
clinical staging can be effectively used even without the
access to CD4 counts or other laboratory testing. But it
 Clinical Stages of HIV
is important to know that the data on CD4 levels is not
a prerequisite to start antiretroviral therapy. It should
only be used with the consideration of clinical stages. In
2005, WHO revised its classification system for different
clinical stages of HIV infections. WHO classification has
developed a 4 stage system and those are 1) Stage I, 2)
Stage II, 3) Stage III, and 4) Stage IV. Description of
different stages has been given below (Table 1).
Table 1: Clinical Stages of HIV Infections: Common Signs and
Symptoms
Stage Signs and symptoms
Stage I
Primary HIV infection Asymptomatic
(Seroconversion) Acute retroviral syndrome
CD4 >500 cells/mm3
Stage II
Asymptomatic Phase Moderate weight loss
Recurrent respiratory tract infections
Herpes zoster
Angular cheilitis
Recurrent oral ulcerations
Papular pruritic eruptions
Seborrhoeic dermatitis
Fungal nail infections of fingers
CD4 >350-499 cells/mm3
Stage III
Generalized Severe weight loss
Lymphadenopathy Unexplained chronic diarrhoea
Unexplained persistent fever
Oral candidiasis
Oral hairy leukoplakia
Pulmonary tuberculosis (TB)
Acute stomatitis, gingivitis or periodontitis
CD4 >200-349 cells/mm3
Stage IV
Symptomatic Phase HIV wasting syndrome
Pneumocystis pneumonia
Chronic herpes simplex infection
Oesophageal candidiasis
Extrapulmonary TB
Kaposi’s sarcoma
Central nervous system toxoplasmosis
HIV encephalopathy, etc.
CD4 <200 cells/mm3
(Adopted from WHO Guideline, 2005, www.who.int/hiv/pub)
Stage I: Primary HIV Infection or Seroconversion:
Primary HIV infection also known as Acute HIV
infection which occurs within 2-4 weeks after initial
exposure to HIV. During this phase large amounts of
virus particles are being produced in the body and they
are present in peripheral blood of the patients. At this
time our immune system responds to protect the host
by producing antibodies against HIV as well as increase
in cytotoxic T lymphocytes. This process is also known
as Seroconversion. At this stage the common symptoms
are mild influenza like symptoms e.g. fever, diarrhea,
sore throat, headaches, etc. >65% cases of HIV infection
are presented with these symptoms. Diagnosis of this
stage is usually based on detection of HIV antigens or
anti-HIV antibodies in blood samples. Confirmatory
Biolixir, 2011, Volume 1: 29-31
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tests are recommended to the patients who turn out to
be negative but have known history to be classified as
high-risk behavior.
Stage II: Asymptomatic Stage: Seroconversion stage is
followed by asymptomatic stage which lasts about ten
years. During this stage viral replication slows down but
does not stop. In the peripheral blood HIV level drops
to very low levels, although, antibodies against HIV can
be detected in blood on regular basis. The CD4 T-cell
counts are usually above 500 cells/mm3. Some patients
also show CD4 T-cell count below 500 cells/mm3.
This phase can be further extended in HIV seropositives
with the right choices of anti-retroviral treatments. In
the present time this stage can be prolonged even up to
20 years post HIV infection with the administration of
improved anti-retroviral drugs. The main objective of
any treatment strategy at this stage is to keep the viral
replication to minimal levels, so that immune-status
deterioration can be minimized.
Stage III: Persistent Generalized Lymphoadenopathy:
There are usually no signs or symptoms present in this
phase, however, there may be a persistent generalized
lymphoadenopathy which lasts for 3 months or more
at atime. It causes swollen nodes, which are usually
>1cm in diameter. The patient looks otherwise healthy,
non-specific adenopathy may persist, but lymph node
biopsy is not recommended as routine.
Stage IV: Symptomatic Stage: Symptomatic HIV
infection is mainly presented with higher incidences of
various opportunistic infections and AIDS associated
cancers. This stage of HIV infection is often characterized
with multi-system disease and infections which affects
all body systems. A rapid decline in immune-status is
observed due to enhanced HIV replication leading to
rapid progression of various diseases. Some constitutional
symptoms like fever, malaise, etc. appear at this stage,
but they can be easily treated. At this stage it is difficult
to control HIV replication. The choices for therapeutic
interventions for the improvement of health status of
patients are either limited or not very useful. These
symptoms are signs of terminal illness and require
counseling of the patient about the final outcome of
the disease rather than keeping patients in dark about
the outcome.
WHO and CDC have to keep updating their classification
for clinical stages of HIV infections, as time passes we
are noticing new clinical symptoms are emerging in long-
Page – 31
term HIV seropositives to name a few is neuroAIDS and
difference in spectrum of opportunistic infections from
one geographical location to other due to prevalence of
entirely different microbes.