HIV/AIDS AND PRINCIPLES

OF HAART
Introduction
• AIDS was first recognized in the US in the summer of
1981, when the U.S. CDC reported the unexplained
occurrence of
 Pneumocystis jiroveci pneumonia in five previously
healthy homosexual men in Los Angeles and
 Kaposi's sarcoma (KS) with or without P. jiroveci
pneumonia in 26 previously healthy homosexual men
in New York and Los Angeles.
In 1983, human immunodeficiency virus (HIV) was
isolated from a patient with lymphadenopathy, and
In 1984 it was demonstrated clearly to be the
causative agent of AIDS.
Epidemiology
• HIV infection/AIDS is a global pandemic, with cases
reported from virtually every country.
• Exploding pandemic
• Infected ˃ 50 million people around the world
• Has killed over 22 million people
• An estimated 95% of people living with HIV/AIDS reside in
low- and middle-income countries; ~50% are female, and
3.2 million are children <15 years
• In 2013, an estimated 2.1 million new cases of HIV
infection occurred worldwide, including 240,000 among
children <15 years;
• About 40% of new infections were among persons under
age 25
•
•
In Ethiopia
 The first evidence of HIV epidemic in Ethiopia -
1984.
 ART began in Ethiopia in 2003 and free ART was
launched in 2005
 National HIV prevalence is 1.1% (2016 Single
point HIV related estimates and projections)
 The recent 2011 EDHS shown that
• urban prevalence is 4.2% which is seven times
higher than that of the rural (0.6%).
• the HIV prevalence varies from region to region
ranging from 0.9% in SNNPR to 6.5% in
National HIV Epidemiology
•
From table above
• The prevalence and the incidence are dropping
• Morbidity and mortality have decreased
• Number of children with HIV is dropping
• ART need is expected to decrease
Etiologic Agent
• HIV is the etiologic agent of AIDS;
 it belongs to the family of human retroviruses
(Retroviridae) and the subfamily of lentiviruses.
 Nononcogenic lentiviruses cause disease in other animal
species, including sheep, horses, goats, cattle, cats, and
monkeys.
The four retroviruses known to cause human disease
belong to two distinct groups:
• the human T lymphotropic viruses (HTLV)-I and HTLV-II,
which are transforming retroviruses; and
• the human immunodeficiency viruses, HIV-1 and HIV-2,
which cause cytopathic effects either directly or indirectly
• HIV type (distinguished genetically)
• HIV-1 -> worldwide pandemic (~ 40 M people)
• HIV-2 -> isolated in West Africa; causes AIDS much more
slowly than HIV-1 but otherwise clinically similar
•
• HIV-1 M subgroups (clades)
• >10 identified (named with letters A to K)
• Descended from common HIV ancestor
• One clade tends to dominate in a geographic region
• Clades differ from each other genetically
• Different clades have different clinical & biologic behavior
• Clade C, which is the most common clade in Ethiopia, causes
a fast-progressing infection.
• Geographic distribution of HIV group M clades
• A in Central Africa
• B in North American, Australia, and Europe
• C in Southern and Eastern Africa (Ethiopia)
Morphology of HIV
•
• HIV is an enveloped positive stranded RNA virus that
measures 120 nm in diameter and consists of a lipid
bilayer with uniformly arranged 72 spikes or knobs of
Glycoproteins
•ƒThese two glycoproteins gp41 and gp120 which play an
important role when the virus attaches to its host cells
• ƒThe viral capsid (core) which contains two single
stranded viral RNA and an important enzyme for the virus
called reverse transcriptase enzyme
• ƒThe reverse transcriptase enzyme plays an important
step in the life cycle of the virus.
 It converts the single stranded viral RNA into double
stranded DNA ( this process is called reverse
Replication Cycle of HIV
 hallmark is the reverse transcription of its genomic RNA
to DNA by the enzyme reverse transcriptase.
begins with the high-affinity binding of the gp120 protein
via a portion of its V1 region near the N terminus to its
receptor on the host cell surface, the CD4 molecule
 The CD4 receptors are present on various types of blood
cells including lymphocytes, macrophages, monocytes,
tissue cells (e.g. Dendritic cells in the genital tract and
ano-rectal region) and glial cells of brain
• Successful entry of the virus to a target cell also requires
cellular co-receptors
• The two major co-receptors for HIV-1 are CCR5 and
CXCR4.
 use of one or the other or both receptors by the virus for
entry into the cell is an important determinant of the
cellular tropism of the virus
• ƒThe receptor and co-receptors of CD4 cells interact with
HIV’s gp-120 and gp-41 proteins during entry into a cell
Phases of HIV Replication;
• 1 ) Attachment /binding and fusion of the virus to the
host cells
The receptor and co-receptors of CD4 cells interact with
HIV’s gp-120 and gp-41 proteins during entry into a cell
• 2) Uncoatting of the viral capsid and release of Viral RNA
into the cytoplasm of the host cell
• 3) Reverse transcription: Viral RNA is converted in to
double stranded DNA by reverse transcriptase enzyme
• 4) Translocation : viral DNA is imported to cell nucleus
• 5) Integration of proviral DNA to host-cell DNA
• 6) Cellular activation causes transcription (copying) of
HIV DNA back to RNA
• 7) Viral Assembly: HIV assembled under cell membrane
and buddes from cell
• 8) Maturation :Viral Protease enzymes cleave longer
proteins in to important viral proteins and help to convert
immature viral particle into and infectious HIV
Transmission of HIV
•
o Sexual Transmission
 HIV infection is predominantly a sexually transmitted
disease (STD) worldwide
Receptive homosexual intercourse has increased risk of
transmitting the virus per act than heterosexual
 viral load and the presence of ulcerative genital diseases
influence the efficiency of heterosexual transmission of
HIV
Females have increased risk of acquiring the virus than
males in heterosexual act.
o Transmission by Blood and Blood Products
 HIV can be transmitted to individuals who receive ;
HIV-tainted blood transfusions,
blood products, or
 transplanted tissue
 IV Drug Users who are exposed to HIV while sharing
injection paraphernalia such as needles, syringes, the
water in which drugs are mixed
o Occupational Transmission of HIV:
 is a small but definite occupational risk of HIV
transmission with HIV-containing materials, particularly
when sharp objects are used
 risk of HIV transmission following skin puncture from a
needle or a sharp object that was contaminated with blood
from a person with documented HIV infection is 0.3% and
after a mucous membrane exposure it is 0.09%
o Maternal-Fetal/Infant Transmission
 can be transmitted from an infected mother to her fetus
during pregnancy,……………….. 23–30%
 during delivery, …………………50–65%
by breast-feeding……………….. 12–20%
o Transmission by Other Body Fluids
 There has been no firm evidence for transmission by
saliva, urine, tears, nonsexual contact in which blood is
not exchanged, or by an insect bite.
Pathogenesis
• HIV primarily disrupts the hemostasis of the immune
system
• When the mucosa is portal of entry for HIV the first cells to
be affected are dendritic cells
• These cells process the antigen introduced and transport
it to the lymphatic tissue, but are not themselves infected
• Within the lymphoid tissue the virus selectively binds with
cells that express CD4 receptor mainly helper T cells and
cells of monocyte –macrophage lineage
• Other cells bearing CD4, such as microglia, astrocytes,
oligodendroglia are also affected
 CD4+ lymphocytes migrate to the lymphatic tissue in
response to viral antigens and then become activated and
proliferate, making them highly susceptible to HIV
infection.
 This antigen-driven migration and accumulation of CD4
cells within the lymphoid tissue may contribute to the
generalized lymphadenopathy characteristic of the acute
retroviral syndrome
 When HIV replication reaches a threshold (usually within
3-6 wk from the time of infection), a burst of plasma
viremia occurs.
 This intense viremia causes flu or mononucleosis-like
symptoms (fever, rash, lymphadenopathy, arthralgia) in
• Within 2-4 months of infections the humeral and cellular
immunity response will be established ,and there will be
decrease in viral load
• And the pateint will have a time of clinical latency
• The primary immunopathogenic lesion in HIV infection
involves CD4+ T cells, and the range of CD4+ T cell
abnormalities in advanced HIV infection is broad.
• The defects are both quantitative and qualitative and
ultimately impact virtually every limb of the immune
system,
indicating the critical dependence of the integrity of the
immune system on the inducer/helper function of CD4+ T
cells.
•
ESTABLISHMENT OF CHRONIC INFECTION
• HIV is a unique infection in that, though the body reacts
by producing antibodies to destroy the virus, the virus is
not cleared, except partially in the early period of infection
• A chronic infection is established, and it persists with
varying degrees of viral replication.
• Viral replication is continuous in all stages infection.
• There is no virological latency.
o Despite robust immune reaction, HIV evades elimination
by the immune system and a chronic infection is
established
• Some of the mechanisms are:
ƒHigh level of viral mutation – HIV has an extraordinary
ability to mutate
 Large pool of latently infected cells that cannot be
eliminated by viral-specific CTLs
Virus homes in lymphoid organs, while antibody is in the
circulation
ƒExhaustion of CD8 T-lymphocytes by excessive antigen
stimulation
ƒHIV attacks CD-4 T-cells, which are central to both
Clinical Manifestations
• The clinical consequences of HIV infection encompass a
spectrum ranging from an acute syndrome associated
with primary infection to a prolonged asymptomatic state
to advanced disease
• There are mainly three phases in the natural course of
HIV.
• 1.Acute HIV syndrome
• 2.Peroid of clinical latency or asymptomatic period
• 3.Peroid of advanced clinical disease
The Acute HIV Syndrome
• It is estimated that 50–70% of individuals with HIV
infection experience an acute clinical syndrome 3–6
weeks after primary infection .
• A flue like syndrome in which symptoms persist from one
two several weeks and gradually subside
as an immune response to HIV develops and the levels of
plasma viremia decrease
 Approximately 10% of patients manifest a fulminant
course of immunologic and clinical deterioration after
primary infection, even after the disappearance of initial
symptoms.
•
•
 The Asymptomatic Stage—Clinical Latency

• Although the length of time from initial infection to the

development of clinical disease varies greatly, the median
time for untreated patients is 10 years.
• HIV disease with active virus replication is ongoing and
progressive during this asymptomatic period.
• The rate of disease progression is directly correlated with
HIV RNA levels.
Patients with high levels of HIV RNA in plasma progress
to symptomatic disease faster than do patients with low
levels of HIV RNA
• Some patients referred to as long-term nonprogressors;
 show little if any decline in CD4+ T cell counts over
extended periods of time.
• These patients generally have extremely low levels of HIV
RNA; a subset, referred to as elite nonprogressors,
exhibits HIV RNA levels <50 copies per milliliter.
• During the asymptomatic period of HIV infection, the
average rate of CD4+ T cell decline is 50/L per year
Symptomatic Disease
• Symptoms of HIV disease can appear at any time during
the course of HIV infection.
• The more severe and life-threatening complications of HIV
infection occur in patients with CD4+ T cell counts <200/L
Rate of progression of disease
• Rapid progressors: After the initial infection patients
progress fast and develop OIs and die within 2-3 years.
Account for 15 % of all patients
• Normal Progressors: After the initial primary infection
patients remain health for 6- 8 years before they start
having overt clinical manifestations: account for 80 % of
all patients
• Long term survivors: Patients who remain alive for 10-
15 years after initial infection.
• Long term non progressors: This is individuals who
have been infected with HIV for > 10 years. Their CD4
count may be in the normal range and they may remain
clinically stable for several years
What affects progress of the
disease?
• Viral set point: The level of steady-state viremia (set-
point) at six months to one year after infection, has an
important prognostic implication for progression of HIV
disease
 Those with a high viral set-point have faster progression
to AIDS, if not treated
• ƒImmune response
• High CD8 slow progression
• Low CD8 rapid decline
• ƒViral type-HIV 2 slow course
• ƒConcomitant conditions
• Malnutrition hastens the progression of HIV
• Chronic infectious conditions e.g. Tuberculosis
WHO STAGING OF AIDS
Why is clinical staging important?

Assess disease severity

Monitor disease progression

Criteria for ARV therapy

WHO Stage I
o Asymptomatic or
oPersistent generalized lymphadenopathy
 Swollen glands (>1cm) in two or more areas outside the groin, >3mo
 Lymph nodes are firm, painless
 Occurs in the back of neck, under the jaw, and in armpit
WHO Stage II
• Moderate unexplained weight loss (<10% of
presumed or measured body weight)
• Recurrent respiratory tract infections (RTIs,
sinusitis, bronchitis, otitis media, pharyngitis)
• Herpes zoster
• Angular cheilitis
• Recurrent oral ulcerations
• Papular pruritic eruptions
• Seborrhoeic dermatitis
• Fungal nail infections of fingers
WHO Stage III
• Severe wt loss (>10% of body wt)
• Unexplained chronic diarrhea for > one month
• Unexplained persistent fever (for > one month)
• Oral candidiasis
• Oral hairy leukoplakia
• Pulmonary TB diagnosed in last two yrs
• Severe presumed bacterial infections (e.g. pneumonia,
empyema, pyomyositis, bone or joint infection, meningitis,
bacteremia)
• Acute necrotizing ulcerative stomatitis, gingivitis or
periodontitis
• Unexplained anemia (<8 g/dl), and or
• neutropenia (<500/mm3) and or
• thrombocytopenia (<50 000/ mm3) for more than one month
WHO Stage IV
• HIV wasting syndrome
• Pneumocystis pneumonia
• Recurrent severe or radiological bacterial pneumonia
• Chronic herpes simplex infection (orolabial, genital or
anorectal of more than one month’s duration)
• Esophageal candidiasis
• Extra pulmonary TB
• Kaposi’s sarcoma
• CNS toxoplasmosis
• HIV encephalopathy
• Extra pulmonary cryptococcosis including meningitis
• Disseminated non-tuberculous mycobacteria infection
• Progressive multifocal leukoencephalopathy (PML)
WHO Stage IV….
• CMV infection (retinitis or of an organ other than liver, spleen
or lymph nodes)
• Any disseminated mycosis (e.g. histoplasmosis,
coccidiomycosis, penicilliosis)
• Recurrent non - typhoidal salmonella septicemia
• Lymphoma (cerebral or B cell non-Hodgkin)
• Invasive cervical carcinoma
• Visceral leishmaniasis
• Candida of trachea, bronchi or lungs
• Cryptosporidiosis
• Isosporiasis
• Visceral herpes simplex infection
HIV wasting syndrome
• Weight loss >10% body weight
plus
• Unexplained chronic diarrhea (>1 mo) or

• Unexplained fever (>1 mo) plus

chronic weakness
Diagnosis of HIV Infection
• The diagnosis of HIV infection depends on the
demonstration of
 antibodies to HIV and/or
the direct detection of HIV or
one of its components( antigen or viral nucleic acid)
• Antibodies to HIV generally appear in the circulation 3–12
weeks following infection.
 HIV antibody tests-
• detect antibodies formed by the immune system against
HIV
• A common antibody test is the ELISA, also referred to as
an enzyme immunoassay(EIA).
• This assay is an extremely good screening test with a
sensitivity of >99.5%
• The fourth-generation EIA tests combine detection of
antibodies to HIV with detection of the p24 antigen of HIV.
• While the EIA is an extremely sensitive test, it is not
optimal with regard to specificity.
• Among the factors associated with false-positive
EIA tests are antibodies to class II antigens (such
as may be seen following pregnancy, blood
transfusion, or transplantation), autoantibodies,
hepatic disease, recent influenza vaccination, and
acute viral infections
• Positive EIA results should be confirmed by western blot
assay.
• This assay takes advantage of the fact that multiple HIV
antigens of different, well-characterized molecular weights
elicit the production of specific antibodies
o Rapid HIV antibody testes
• ƒRapid tests have reasonably good sensitivity and
specificity ( >99 % )
• ƒCan be done by less skilled personnel and the
interpretation of results is easy
• ƒTest result can be made available in < 30 minutes
• ƒBecause of these advantages of rapid tests ,WHO has
recommend a series of Rapid HIV antibody testes to be
done to diagnose HIV infection.
National Algorithm: Ethiopia
•
•
o Detection of Viral Antigen in Blood and Body Fluids
The p24 antigen assay detects the viral capsid (core)
p24 protein in blood which is detected earlier than HIV
antibody during acute infection
o DNA – PCR
Is an extremely sensitive test -can detect 1-10 copies of
HIV proviral DNA per ml of blood
Iƒt uses PCR technology to amplify proviral DNA
ƒThis test is costly and needs sophisticated instruments
and highly skilled professional
It is highly sensitive and the chance of false positivity is
high. hence it should not be used for making initial
diagnosis of HIV infection
 It is often used
• i. To make early diagnosis of HIV in HIV exposed infants
as serology tests are unable to diagnose HIV till the infant
is 18 months old
• ii. To diagnose or confirm virologic failure in patients who
are not responding to ART
• iii. When there is indeterminate serology
•
ROUTINE TESTS
• Additional tests that should be done is patients with HIV
infection include:
• ƒ
HBV , HCV
• ƒ
CBC and ESR
• SGOT/AST and SGPT/ALT
• ƒ
Serum Creatinine ,BUN
• ƒ
Syphilis serology: RPR
• ƒ
AFB chest X-Ray where possible
• Stool examination for parasites
• ƒ
Malaria blood slide
• ƒ
Pregnancy test for women in child bearing age
Laboratory Markers of HIV
Infection
• Viral load
• Marker of HIV replication rate
• Number of HIV RNA copies/mm3 plasma

• CD4 count
• Marker of immunologic damage
• Number of CD4 T-lymphocyte cells/mm3 plasma
• Median CD4 count in HIV negative Ethiopians is significantly
lower than that seen in Dutch controls
• Female 762 cells/mm3 (IQR 604-908)
• Male 684 cells/mm3 (IQR 588-832)
Antiretroviral Therapy(ART)
• Combination antiretroviral therapy (cART), also referred
to as highly active antiretroviral therapy (HAART),
 is the cornerstone of management of patients with HIV
infection.
• Drugs used for the treatment of HIV will interrupt the life
cycle of the virus at one or more step.
• Is not a cure for HIV.
 If treatment is stopped, the virus will continue to replicate
 It cannot eliminate HIV completely from the body.
o Goals of ART:
1) Restoring and/or preserving immune function as reflected by CD4
cell measures;
2) Maximally and durably suppressing viral replication;
3) Preventing emergence of viral drug-resistance mutations;
4) Minimizing drug-related toxicity;
5) Maintaining normal physical growth and neurocognitive
development;
6) Reducing the risk of sexual transmission to discordant
partners in adolescents who are sexually active;
7) Reducing the risk of vertical transmission
o Nucleoside reverse
transcriptase inhibitors ( NRTIs)
• Lamivudine (3TC) Stavudine ( d4t )
• Zidovudine (AZT Abacavir ( ABC)
• Didanosine (DDI ) Zalcitabin ( DDC )
• Emtricitabine (FTC) Tenofovir (TDF ),
Mechanism of Action: Structurally these drugs resemble
naturally occurring nucleosides and break the formation of
viral DNA by breaking the chain ( chain breakers )
o Non-nucleoside reverse
transcriptase inhibitors (
NNRTIs
• Nevirapine (NVP,)
• Efavirenz (EFV,)
• Delavirdine (DLV,) rarely used
Mechanism of Action :inhibit the active site of Reverse
transcriptase enzyme
o Protease Inhibitors
• Lopinavir + Ritonavir (Kaletra®) Nelfinavir
• Saquinavir- Indinavir Amprenavir
• Fosamprenavir Atazanavir
• Ritonavir
Mechanism of Action: Inhibit viral assembly by blocking
the enzyme protrease
PIs are mainly used as second line drugs in resource
limited settings as these drugs are expensive and most
formulations need refrigeration.
•2NRTI+ 1NNRTI(PI)
 Preparing people living with HIV for ART

• The key elements that need to be addressed during

preparation are:
• 1. All clients to be started on ART need to be retested for
HIV to verify their status.
• 2. Complete assessment (i.e. history taking, complete
physical, relevant laboratory tests.
• 3. Screening and proper management of opportunistic
infections and comorbidities.
• 4. WHO clinical staging
• 5. Pregnancy status, family planning and contraception
• 6. Support for disclosure and partner notification
• 7. Risk reduction, counseling and combination HIV
prevention approaches
What to expect in the first months
• Clinical and immunological improvement and viral
suppression
• opportunistic infections (OIs) and/or immune
reconstitution inflammatory syndrome (IRIS) may develop,
• early adverse drug reactions, such as drug
hypersensitivity, especially in the first three months of
treatment.
• ART significantly decreases mortality overall, but death
rates are also highest in the first three months of ART.
these complications are most common when the people
starting ART have,
• advanced HIV disease with severe immunodeficiency
and
When to start ART
•
 WHO, for the first time, recommends that all people living
with HIV be provided with ART.
This will bring us one step closer to achieving universal
access to HIV treatment and care and ending AIDS as a
public health threat.
 The 90–90–90 targets include ;
90% of the people living with HIV know their HIV status,
90% of the people who know their HIV status receiving
ART
90% of the people receiving ART having suppressed viral
loads.
First Line Regimen
•
Post-exposure prophylaxis
• HIV PEP should be offered and initiated as early as
possible in all individuals with an exposure that has the
potential for HIV transmission, preferably within 72 hours.
• For individuals who may not be able to access services
within this time, providers should consider the range of
essential interventions and referrals that should be offered
to clients presenting after 72 hours.
• Exposures that may warrant HIV PEP include
the following:
body fluids: blood, bloodstained saliva, breast milk,
genital secretions and cerebrospinal, amniotic, peritoneal,
synovial, pericardial or pleural fluid.
types of exposure: 1) mucous membrane, i.e. sexual
exposure; splashes to eye, nose, or oral cavity; and 2)
parenteral.
• Exposures that do not require HIV PEP
include the following:
when the exposed individual is already HIV positive;
when the source is established to be HIV negative; and
exposures to body fluids that do not pose a significant
risk, i.e. tears, non-bloodstained saliva, urine and sweat
•
•
Monitoring treatment response
Viral load monitoring
• Routine viral load monitoring should be started after 6
months of treatment and then every 12 months.
 CD4 monitoring.
• 1. All patients need to have base line CD4 testing done to
determine eligibility for OI prophylaxis.
• 2. CD4 monitoring should be continued for all patients
who are put on co-trimoxazole prophylaxis
• 3. In situations where viral load monitoring is not
accessible/possible continue with CD4 monitoring to
assess for immunologic failure.
WHO definition of clinical, immunological and virologic
treatment failure

•
•
Second-line ART for adults and adolescents

•
Immune reconstitution inflammatory syndrome

Describes collection of inflammatory disorders associated

with
paradoxical worsening of preexisting infectious
processes or unrecognized pre-existing infection
(“unmasking” IRIS) in the setting of improving
immunologic function following the initiation of HAART in
HIV-infected individuals
 spectrum of clinical signs and symptoms thought to be
associated with immune recovery brought about by a
response to ART.
It occurs among 10–30% of the people initiating ART,
usually within the first 4–8 weeks after initiating therapy
Preexisting infections in individuals with IRIS may have
• If immune function improves rapidly following the
commencement of HAART,
systemic or local inflammatory reactions may occur at the
site or sites of the preexisting infection.
this inflammatory reaction is usually self-limited,
especially if the preexisting infection is effectively treated.
However, long-term sequelae and fatal outcomes may
rarely occur, particularly when neurologic structures are
involved.
 It should be considered only when the presentation
cannot be explained by a new infection, expected course
of a known infection or drug toxicity.
The likelihood and severity of IRIS correlates with two
interrelated factors:
• 1) the extent of CD4+ T cell immune suppression prior to
the initiation of HAART and
• 2) the degree of viral suppression and immune recovery
following the initiation of HAART.
RISK FACTORS
• A low CD4+ cell count (<50 cells/mm3) at ART initiation,
• Disseminated opportunistic infections or tumors and
• A shorter duration of therapy for opportunistic infections
before ART starts
• Degree of immunologic improvement on ART
• A higher level of viremia at baseline and the degree of
viral decline on ART
• Use of a "boosted" protease inhibitor – PI have;
immunomodulatory effects on T cell lymphoproliferation
and apoptosis;
enhance macrophage production of proinflammatory
cytokines
CLINICAL MANIFESTATIONS
• The clinical features of IRIS are strongly related to the
type and location of preexisting opportunistic infection.
• Furthermore, preexisting infections may or may not be
clinically apparent prior to the initiation of ART.
• Symptoms of IRIS can be localized or systemic.
• About 3/4 of patients with mycobacterial or cryptococcal-
related immune reconstitution syndromes develop fever
• In contrast, fever occurs infrequently in IRIS related to
previously recognized or subclinical infection with
cytomegalovirus.
• The median time to IRIS diagnosis in one trial was 33
days .
DIAGNOSTIC CRITERIA FOR IRIS
o Most or all of the following features should be present in
order to make the diagnosis:
 The presence of AIDS with a low pretreatment CD4 count
(< 100 cells/µL) , except IRIS secondary to preexisting M.
tuberculosis infection (may occur in individuals with CD4
counts >200).
A positive virologic and immunological response to ART .
The absence of evidence of drug-resistant infection,
bacterial superinfection, drug allergy or other adverse
drug reactions, patient noncompliance, or reduced drug
levels due to drug-drug interactions or malabsorption after
appropriate evaluation for the clinical presentation.
The presence of clinical manifestations consistent with an
Management of IRIS
• The most important steps to reduce the development of
IRIS include:
• earlier HIV diagnosis and initiation of ART before a
decline to below 200 CD4 cells/mm3;

• improved screening for opportunistic infections

before ART, especially TB and Cryptococcus;

• and optimal management of opportunistic infections

before initiating ART.
• Timing of ART in people with opportunistic infections
requires balancing a greater risk of IRIS after early
initiation against continuing high mortality if ART is
delayed.

• Patients should generally be treated for the underlying

opportunistic infection as soon as possible

• Continuation of ART when IRIS occurs

• Careful use of anti-inflammatory agents.
THANK YOU!