Chapter 173: Human Immunodeficiency Virus Disease: AIDS and
Related Disorders
3D Batch 2008
AIDS (reported by US Centers for Disease Control and Prevention
or CDC)
• Pnuemocystis carinii pneumonia – 5 previously healthy
homosexual men in Los Angeles
• Kaposi Sarcoma – 26 previously healthy homosexual men in
New York and Los Angeles
AIDS
• recognized in male and female injection drug users
• recipients of blood transfusions
• hemophiliacs
• most likely etiologic agent - microbe transmissible by sexual
(homosexual and heterosexual) contact and blood or blood
products
Human Immunodeficiency Virus (HIV)
• isolated from a patient with lymphadenopathy in 1983
• demonstrated clearly to be the causative agent of AIDS in
1984
• ELISA was developed in 1985, which led to an appreciation
of the scope and evolution of the HIV epidemic
• current CDC classification system for HIV-infected
adolescents and adults categorizes persons on the basis of
clinical conditions associated with HIV infection and CD4+ T
lymphocyte counts
o three ranges of CD4+ T lymphocyte counts
o three clinical categories
o represented by a matrix of nine mutually exclusive
categories (Tables 173-1 and 173-2)
o any HIV-infected individual with a CD4+ T cell
count of <200/μL has AIDS regardless of the
presence of symptoms or opportunistic diseases
• once individuals have had a clinical condition in category B,
their disease cannot again be classified as category A, even
if the condition resolves; the same holds true for category C
in relation to category B
Etiologic Agent (HIV)
• belong to the family of retroviruses (Retroviridae) and the
subfamily of lentiviruses
• the four recognized human retroviruses belong to two
distinct groups
o human T lymphotropic viruses (HTLV) I and HTLV
II which are transforming retroviruses
o human immunodeficiency viruses (HIV 1 and HIV
2) which are cytopathic viruses
• most common cause of HIV disease throughout the world is
HIV 1
• HIV 1 comprises several subtypes with different geographic
distributions
• HIV 2 was first identified in West African patients and was
originally confined to the West Africa
• HIV 1 and HIV 2 are zoonotic infections
• HIV 2 is more closely related to phylogenetically to the
simian immunodeficiency virus (SIV) found in sooty
mangabeys
• HIV 1 likely originated from the Pan troglodytes troglodytes
species of chimpanzees
Morphology of HIV
• icosahedral structure seen in electron microscopy containing
numerous external spikes formed by the two major envelope
proteins, the external gp120 and the transmembrane gp41
• virion buds form the surface of the infected cell and
incorporates a variety of host proteins, including major
histocompatibility complex (MHC) class I and II antigens into
its lipid bilayer
Replication Cycle of HIV
• HIV is an RNA virus whose hallmark is the reverse
transcription of its genomic RNA to DNA by the enzyme
reverse transcriptase
• replication cycle 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
• CD4 molecule is a 55-kDa protein found predominantly on a
subset of T lymphocytes that are responsible for helper or
inducer function in the immune system and is expressed on
the surface of monocytes/macrophages and
dendritic/Langerhans cells
• once gp120 binds to CD4, the gp120 undergoes a
conformational change that facilitates binding to one of a
group of co-receptors
• the two major co-receptors for HIV 1 are CCR5 and CXCR4,
both of which belong to the family of seven transmembrane
domain G protein-coupled cellular receptors
• certain dendritic cells express a diversity of C-type lectin
receptors on their surface, one of which is called DC-SIGN,
that bind with high affinity to the HIV gp120 envelope protein,
allowing the dendritic cell to facilitate the binding of virus to
the CD4+ T cell upon engagement of dendritic cells with
CD4+ T cells
• the conformation of the viral envelope changes dramatically,
and fusion with the host cell membrane occurs via the newly
exposed gp41 molecule penetrating the plasma membrane
of the target cell and then coiling upon itself to bring the
virion and target cell together
• following fusion, the HIV genomic RNA is uncoated and
internalized into the target cell
• the reverse transcriptase enzyme, which is contained in the
infecting virion, then catalyzes the reverse transcription of
the genomic RNA into double strand DNA
• the DNA translocates to the mucleus, where it is integrated
in a random fashion into the host cell chromosomes through
the action of another virally encoded enzyme, integrase
• sites of HIV integration into the nuclear DNA are preferential
for active genes and regional hotspots
• cellular activation plays an Important role in the life cycle of
HIV and is critical to the pathogenesis of HIV disease
• following initial binding and internalization of virions into the
target cell, incompletely reverse-transcribed DNA
intermediates are labile in quiescent cells, unless cellular
activation occurs shortly after infection
• some degree of activation of the host cell is required for the
initiation of transcription of the integrated proviral DNA into
either genomic RNA or mRNA
• activation of HIV expression from the latent state depends
on the interaction of a number of cellular and viral factors
• following transcription, HIV mRNA is translated into proteins
that undergo modification through glycosylation,
myristylation, phosphorylation, and cleavage
• the viral particle is formed by the assembly of HIV proteins,
enzymes, and genomic RNA at the plasma membrane of the
cells
• budding of the progeny virion occurs through specialized
regions in the lipid bilayer of the host cell membrane known
as lipid rafts, where the core acquires its external envelope
• the virally encoded protease then catalyzes the cleavage of
the gag-pol precursor to yield the mature virion
• each point in the replication cycle of HIV is a real or potential
target for therapeutic intervention
• the reverse transcriptase and protease enzymes have
proven clinically to be susceptible to pharmacologic
disruption
HIV Genome
• HIV 1 has genes that encode the structural proteins of the
virus
• gag encodes the proteins that form the core of the virion
(including p24 antigen)
• pol encodes the enzymes responsible for reverse
transcription and integration
• env encodes the envelope glycoproteins
• HIV is more complex than other retroviruses because it
contains at least six other genes (tat, rev, nef, vif, vpr, vpu),
which code for proteins involved in the regulation of gene
expression
• long terminal repeats (LTRs), which contain regulatory
elements involved in gene expression
• major difference between the genomes of HIV 1 and HIV 2 is
the fact that HIV 2 lacks the vpu gene and has a vpx gene
not contained in HIV 1
Molecular Heterogeneity of HIV 1
• HIV can evolve by several means, including simple base
substitution, insertions and deletions, recombination and
gain and loss of glycosylation sites
• the balance of immune pressure and functional constraints
on proteins influences the regional level of variation within
proteins
• envelope which is exposed on the surface of the virion and is
under immune selective pressure from both antibodies and
cytolytic T lymphocytes, is extremely variable, with clusters
of mutations in hypervariable domains
 • in contrast, reverse transcriptase, with important enzymatic
functions, is relatively conserved, particularly around the
active site
• three groups of HIV 1
o group M (major) which is responsible for most of
the infections in the world
o group O (outlier) a relatively rare viral form found
originally in Cameroon, Gabon, and France
o group N first identified in a Cameroonian woman
with AIDS
• HIV 1 is most closely related to viruses isolated from
chimpanzees
• M group comprises nine subtypes, or clades, designated A,
B,C,D,F,G,H,J,K as well as a growing number of major
circulating recombinant forms (CRFs)
• these CRFs range from highly prevalent forms such as the
AE virus, CRF 01, which is predominant in Southeast Asia
and often referred to as E, despite the fact that the parental
E virus has never been found
• the subtypes and CRFs create the major lineages of the M
group of HIV 1
• sub-subtypes was introduced since some subtypes are not
equidistant to one another and others contained sequences
so diverse that they could not properly be considered as the
same subtype
• subtypes A and F are now subdivided into A1 and A2 , F1
and F2
• subtype B viruses, which now differ by up to 17% in their env
coding sequences , are the overwhelmingly predominant
viruses seen in the United States, Canada, certain countries
in South America, western Europe, and Australia
• subtype C viruses, are the most common form worldwide
• in Africa, >75% of strains recovered to date are the following:
A,C,D and C being the most common
• in Asia, HIV 1 isolates of the CRF01 (AE) lineage and
subtypes C and B predominate
• CRF01 (AE) accounts for most infections in southeast Asia,
while subtype C is prevalent in India
TRANSMISSION
Sexual Transmission
• HIV infection is predominantly a sexually transmitted disease
• the most common mode of infection worldwide, particularly
in developing countries, is heterosexual transmission
• HIV has been demonstrated in seminal fluid both within
infected mononuclear cells and in the cell-free state
• appears to concentrate in the seminal fluid, particularly in
situations where there are increased numbers of
lymphocytes and monocytes in the fluid, as in genital
inflammatory states such as urethritis and epididymitis
• has been demonstrated in cervical smears and vaginal fluid
• strong association of transmission of HIV with receptive anal
intercourse, probably because only a thin, fragile rectal
mucosal membrane separates the deposited semen from
potentially susceptible cells in and beneath the mucosa and
trauma may be associated with anal intercourse
• anal intercourse provides at least two modalities of infection
o direct inoculation Into blood in cases of traumatic
tears in the mucosa
o infection of susceptible target cells, such as
Langerhan cells, in the mucosal layer in the
absence of trauma
• vaginal mucosa is several layers thicker than the anal
mucosa and less likely to be traumatized during intercourse,
the virus can be transmitted to either partner through vaginal
intercourse
• infections with microorganisms such as Treponema pallidum,
Haemophilus ducreyi, Herpes simplex virus are important
causes of genital ulcerations linked to transmission of HIV
• pathogens responsible for nonulcerative inflammatory STDs
such as those caused by Chlamydia trachomatis, Neisseria
gonorrhoeae, and Trichomonas vaginalis are also associated
with an increased risk of transmission of HIV infection
• bacterial vaginosis, an infection related to sexual behavior,
may also be linked to an increased risk of transmission of
HIV infection
• in studies conducted in Uganda, the chief predictor of
heterosexual transmission of HIV was the level of plasma
viremia
• lack of circumcision has been strongly associated with a
higher risk of HIV infection
• the highly vascularized inner foreskin tissue contains
contains a high density of Langerhans cells as well as
increased numbers of CD4+ T cells, macrophages, and
other cellular targets for HIV
• the moist environment under the foreskin may promote the
presence or persistence of microbial flora which, via
inflammatory changes, may lead to even higher
concentrations of target cells for HIV in the foreskin
• oral sex is a much less efficient mode of transmission of HIV
than is receptive anal intercourse
• the association of alcohol consumption and illicit drug use
with unsafe sexual behavior, both homosexual and
heterosexual, leads to an increased risk of sexual
transmission of HIV
Transmission by Blood and Blood Products
• HIV can be transmitted to individuals who receive HIV-
tainted blood transfusions, blood products, or transplanted
tissue
• as well as to IDUs who are exposed to HIV while sharing
injection paraphernalia such as needles, syringes, the water
in which drugs are mixed, or the cotton through which drugs
are filtered
• among IDUs, the risk of HIV infection increases with the
duration of drug use; the frequency of needle sharing; the
number of partners with whom paraphernalia are shared,
particularly in the setting of “shooting galleries” where drugs
are sold and large numbers of IDUs may share a limited
number of “works”; co-morbid psychiatric conditions such as
antisocial personality disorder; the use of cocaine in
injectable form or smoked as “crack”; and the use of injection
drugs in a geographic location with a high prevalence of HIV
infection, such as certain inner-city areas
• transfusions of whole blood, packed red blood cells,
platelets, leukocytes, and plasma are all capable of
transmitting HIV infection
• hyperimmune γ globulin, hepatitis B immune globulin,
plasma-derived hepatitis B vaccine, and Rho immune
globulin have not been associated with transmission of HiV
Infection
• the following measures have made the risk of transmission
of HIV infection by transfused blood or blood products
extremely small
o the screening of all blood for HIV nucleic acid, p24
antigen, and/or anti-HIV antibodies
o the self-deferral of donors on the basis of risk
behavior
o the screening out of HIV-negative individuals with
positive surrogate laboratory parameters of HIV
infection, such as hepatitis B and C
o serologic testing for syphilis
• one cannot completely eliminate the risk of transfusion–
related transmission of HIV since current technology cannot
detect HIV RNA for the first 1 to 2 weeks following infection
due to the low levels of viremia
• the chance of infection of a hemophiliac via clotting factor
concentrates has essentially been eliminated because of the
added layer of safety resulting form heat treatment of the
concentrates
Occupational Transmission of HIV: Health Care Workers and
Laboratory Workers
• risk of HIV transmission following skin puncture from a
needle or a sharp object that was contaminated by blood
from a person with documented HIV infection is
approximately 0.3% and after a mucous membrane
exposure it is 0.09%
• an increased risk for HIV infection following percutaneous
exposures to HIV-infected blood is associated with
exposures involving a relatively large quantity of blood, as in
the case of a device, visibly contaminated with the patients
blood, a procedure that involves a needle placed directly in a
vein or artery, or a deep injury
• factors that might be associatred with mucocutaneous
transmission of HIV include exposure to an unusually large
volume of blood, prolonged contact, and a potential portal of
entry
• the risk increases for exposures to blood from patients with
advanced-stage disease, probably owing to the higher titer
of HIV in the blood as well as to other factors, such as the
presence of more virulent strains of the virus
• the use of antiretroviral drugs as postexposure prophylaxis
decreases the risk of infection compared to historic controls
in occupationally exposed health care workers
• the risk of transmission from an infected health care worker
to patients is extremely low
Maternal-Fetal/Infant Transmission
 • HIV infection can be transmitted from an infected mother to
her fetus during pregnancy, during delivery, or by breast-
feeding
• HiV can be transmitted to the fetus as early as the first and
second trimester of pregnancy
• maternal transmission to the fetus occurs most commonly in
the perinatal period based on the following considerations:
o the time frame of identification of infection by the
sequential appearance of classes of antibodies to
HIV (the appearance of HIV-specific IgA antibody
within 3 to 6 months after birth)
o a positive viral culture
o the appearance of p24 antigenemia weeks to
months after delivery, but not at the time of
delivery
o polymerase chain reaction assay of infant blood
following delivery that is negative at birth and
positive several months later
o the demonstration that the first born twin of an
infected mother is more commonly infected than
is the second twin
o evidence of a caesarian section results in
decreased transmission to the infant
• in the absence of prophylactic antiretroviral therapy to the
mother during pregnancy, labor and delivery, and to the
fetus following birth , the probability of transmission of HIV
from mother to infant/fetus ranges from 15%-35%
• the best documented factor that is associated with higher
rates of transmission is the presence of high maternal levels
of plasma viremia
• low maternal CD4+ T-cell counts have also been associated
with higher rates of transmission; however since low levels
of CD4+ T cell counts are often associated with high levels
of plasma viremia, only the level of plasma HIV RNA was
significant
• a prolonged interval between membrane rupture and
delivery is another well-documented risk factor for
transmission
• vitamin A deficiency had been reported to be associated
with higher transmission rates; however, vitamin A
supplements during pregnancy resulted in improved birth
weight and neonatal growth and reduced anemia but did not
affect perinatal transmission of HIV
• current recommendations to reduce perinatal transmission
of HIV include universal voluntary HIV testing and
counseling of pregnant women, antiretroviral prophylaxis
with one or more drugs in cases in which the mother does
not require therapy for her HIV infection, combination
therapy for women who do require therapy, obstetric
management that attempts to minimize exposure of the
infant to the maternal blood and genital secretions, and
avoidance of breast-feeding
• the choice of antiretroviral therapy for pregnant women
should be based on the same considerations used for
women who are not pregnant, with discussion of the
recognized and unknown risks and benefits of such therapy
during pregnancy
• zidovudine alone or in combination with lamivudine, given to
the mother during the last few weeks pf pregnancy or even
during labor and delivery, and to the infant for a week or
less, reduced transmission of the virus by 50% compared to
the placebo
• one important study in Uganda, a single dose of nevirapine
given to the mother at the onset of labor followed by a single
dose to the newborn within 72 hours of birth decreased
transmission by 50% compared with a regimen of
zidovudine
• nevirapine is much cheaper than zidovudine
• breast feeding is an important modality of transmission of
HIV infection in developing countries, particularly with
mothers continue to breast feed for prolonged periods
• factors that increases the likelihood of transmission include
detectable levels of HIV in breast milk, the presence of
mastitis, low maternal CD4+ T cell counts, maternal vitamin
A deficiency
• the risk of HIV infection via breast feeding is highest in the
early months of breast feeding
• intermittent administration of nevirapine, which has a
relatively long half life, to uninfected babies born of infected
mothers decreases the incidence of infection via breast
feeding
Transmission by Other Bodily Fluids
• although HIV can be isolated typically in low titers from
saliva of a small proportion of infected individuals, there is no
convincing evidence that saliva can transmit HIV infection,
either by kissing or through other exposures
• saliva contains endogenous antiviral factors; among these
factors, HIV-specific immunoglobulins of IgA, IgG, and IgM
isotypes are detected readily in salivary secretions of
infected individuals
• large glycoproteins, such as mucins and thrombospondin-1
sequester HIV into aggregates for clearance by the host.
• a number of soluble salivary factors inhibit HIV to various
degrees in vitro, probably by targeting host cell receptors
rather than the virus itself
• secretory leukocyte protease inhibitor (SLPI), blocks HIV
infection in several cell culture systems. And it is found in
saliva at levels that approximate those required for inhibition
of HIV in vitro
• higher salivary levels of SLPI in breast-fed infants were
associated with a decreased risk of HIV transmission
through breast milk
• submandibular saliva reduces HIV infectivity by stripping
gp120 from the surface of virions, and that saliva-mediated
disruption and lysis of HIV-infected cells occurs because of
the hypotonicity of oral secretions
• transmission of HIV by human bite can occur but is a rare
event
• a most unusual form of HIV transmission from infected
children to mothers in the former Soviet Union
• the children (infected through transfusion)were said to have
bleeding sores in the mouth, and the mothers were said to
have lacerations and abrasions on and around the nipples of
the breast resulting from trauma to from the children’s teeth
EPIDEMIOLOGY
HiV Infection and AIDS Worldwide
• HIV infection/AIDS is a global pandemic
• the current estimate of the number of cases of HIV
infection among adults worldwide is approximately 37
million, 2/3 of whom are in sub-Saharan Africa; 50% of
cases are women
• an estimated 2.5 million children younger than age 15
are living with HIV/AIDS
• according to Joint United Nations Programme on
HIV/AIDS (UNAIDS), in 2003 alone there were an
estimated 5 million new cases of infection
worldwide(>14,000 new infections each day) and 3
million deaths from AIDS, making it the fourth leading
cause of mortality worldwide
• the HIV epidemic has occurred in “waves” in different
regions of the world, each eave having somewhat
different characteristics depending on the
demographics of the country
• in addition to HIV 1 subtype B , the predominant
subtype in the United States, HIV subtypes A, AE, AG,
C, D, O have been detected in individuals in the
United States
• it very likely began in sub-Saharan Africa (such as
Zimbabwe and Botswana), which has been particularly
devastated by the epidemic, with the prevalence of
infection in many cities in double digits
• by the year 2015, life expectancy at birth in the seven
countries in Africa with adult HIV prevalence >20% will
be 32 years lower on average than the projected life
expectancy in the absence of AIDS
• India and China, the number of new cases in this
region is accelerating rapidly, and the magnitude of
the epidemic is projected to exceed that of sub-
Saharan Africa in the early part of the twenty-first
century
• the epidemic is also expanding rapidly in the Baltic
States, the Russian Federation, and several Central
Asian Republics
HIV Chapter
I. Pathophysiology and Pathogenesis
 hallmark of HIV disease is a profound immunodeficiency
resulting primarily from a progressive quantitative and
qualitative deficiency of the subset of T lymphocytes (called
helper T cells or inducer T cells)
 helper T cells: defined phenotypically by the presence on its
surface of the CD4 molecule, which serves as the primary
cellular receptor for HIV
 HIV uses 2 major co-receptors for fusion and entry
1. CCR5
2. CXCR4
 When the number of CD4+ T cells declines below a certain
level, the patient is at high risk for developing opportunistic
infections
 A. Primary HIV infection, initial viremia and dissemination of 4. heterozygosity for the RANTES-28G mutation
virus  increases RANTES expression, which is a natural
• The dissemination of virus to lymphoid organ is a major ligand for CCR5 and may thus inhibit infection
factor in the establishment of chronic and persistent
infection IV. Lymphoid organs and HIV pathogenesis
• Route of infection  lymphoid tissues are the major anatomic sites for the
♣ Directly to blood stream establishment and propagation of HIV infection
♣ “locally” via mucosal dendritic cells  virus replication occurs mainly in lymphoid tissue and not in
• Dendritic cells: express a C-type lectin receptor called blood
 lymphadenopathy
DC-SIGN. This binds with high affinity to HIV
1. reflects the cellular activation and immune response to
• In primary HIV infection, virus replication in T cells the virus in the lymphoid tissue
intensifies prior to the initiation of an HIV-specific 2. generally characterized by follicular or germinal center
immune response  burst of viremia hyperplasia
 acute HIV infection
B. Establishment of chronic and persistent infection 1. high level of viral replication
• Persistent virus replication: this is a hallmark of HIV 2. cellular activation
disease 3. virions are trapped on the processes of the follicular
• Evasion of immune system control (mechanisms) dendritic cells (FDC)
♣ Chronicity of HIV  due to
4. electron microscopy reveals:
 fine network of FDCs with many long, finger-like
1. ability to evade elimination and control by the processes
immune system
 secretion of proinflammatory cells, which can
2. ability to mutate
upregulate virus replication
3. high rate of replication
 chronic HIV infection
♣ virus replication and saturation of antigen
1. germinal centers begin to show disruption
presenting cells with viral antigen take place in the
2. electron microscopy reveals
lymphoid tissue
 swollen organelles
♣ downregulation of HLA class 1 molecules by the  FDCs begin to undergo cell death
Nef protein of HIV  inability of immune response 3. Lymph nodes are “burnt out”
to kill the infected cells
♣ conformational masking of receptor-binding sites V. Cellular activation and HIV pathogenesis
 aberrant immune activation is the hallmark of HIV infection
♣ HIV preferentially infects CD4+ T cells  loss of and is a critical component of the pathogenesis of HIV
immune response disease.
♣ Escape of HIV  allows the formation of a large  This activated state shows:
1. hyperactivation of B cells leading to
pool of latently infected cells that cannot be
hypergammaglobulinemia
eliminated by virus-specific CTLs
2. spontaneous lymphocyte proliferation
3. activation of monocyte
C. Latent reservoir of HIV-infected cells: obstacle to the
4. expression of activation markers on CD4+ and CD8+ T
eradication of virus
cells
• The HIV provirus integrates into the genome of the cell
5. lymph node hyperplasia
until an activation signal drives the expression of the
6. secretion of cytokines
HIV transcripts
7. elevated levels of neopterin
• This reservoir may replenish even during treatment
8. beta-2 microglobulin
9. acid-labile interferon
D. Viral dynamics
10. IL-2 receptors
• The early rise in CD4+ T cell numbers following the
11. autoimmune phenomena
initiation of therapy is due to the redistribution of cells
 exogenous factors may increase or decrease HIV replication
into the peripheral blood from other body components
• The half-life of a circulating virion was approximately  increases HIV replication
30-60 minutes and that of productively infected cells 1. HSV type 1
was 1 day 2. CMV
3. human herpes virus 6
• Viral set-point: the level of steady state viremia, at ~1 4. EBV
year 5. HBV
6. adenovirus
E. Clinical latency versus microbiological latency 7. pseudorabies virus
• The slope if this decline is usually a good predictor of 8. HTLV-1
the pattern of the clinical course 9. mycoplasma
• Most patients are entirely asymptomatic while this 10. nematode infection
progressive decline is taking place, and are often 11. mycobacterium tuberculosis
described as being in a state of clinical latency
A. Apoptosis
• Microbiological latency: phase of low-level viremia
1. HIV infection  increase in apoptosis
II. Advanced HIV disease 2. Sequential activation signals delivered to CD4+ T cells
induces apoptosis
 if the CD4+ T cell count falls below a critical level (<200 per 3. HIV can trigger both Fas-dependent and Fas-
microliter) independent pathways of apoptosis
4. The intensity of apoptosis correlates with the general
 the patient becomes highly susceptible to opportunistic
state of activation of the immune system and not with
disease the stage of disease or with viral burden
 definition of AIDS: includes all HIV-infected individuals with 5. Apoptosis of immunocompetent cells contributes to the
CD4+ T cell counts below 200/μL immune abnormlities in HIV disease
III. Long-term survivors and long-term nonprogressors B. Autoimmune phenomena
 long-term nonprogressors: are by definition long-term • Includes antibodies to lymphocytes, platelets and
survivors neutrophils
 long-term survivors: if they remain alive for ≥20 years after • May contribute to thrombocytopenia of HIV disease
initial infection
 genetic mutations that have demonstrated a delay in VI. The Cytokine network in HIV pathogenesis
progression of HIV disease  some cytokines induce HIV expression
1. heterozygosity for the CCR5-Δ32 deletion 1. interleukin 1, 2, 3, 6, 12
 CCR5: major co-receptor for R5 or macrophage- 2. TNF-α, TNF-β
tropic strains of HIV 3. macrophage colonoy stimulating factor
2. heterozygosity for the CCR2-64I mutation 4. granulocyte-macrophage CSF
3. homozygosity for the SDF1-3’A mutation  most consistent and potent inducers: TNF-α, TNF-β and IL-6
 upregulation of SDF-1, which is the natural ligand  suppress HIV expression
for CXCR4, to compete more effectively with X4 or 1. interferon-α and -β
T cell tropic virus

 may either suppress or induce HIV expression
1. transforming growth factor beta,
2. IL-4, IL-10
3. IFN-γ
 CC-chemokines RANTES, macrophage inflammatory protein
(MIP) 1-alpha and MIP 1-beta inhibit infection by and spread
of R5 HIV strains
 Stromal cell derived factor (SDF) 1 inhibits infection by and
spread of X4 HIV strains
 Alpha defensin family can inhibit both R5 and X4 strains
VII. Lymphocyte turnover in HIV infection
 characterized by a profound increase in lymphocyte turnover
 higher rate of turnover corresponds to a higher rate of death
 TRECs (T-cell receptor excision circles): represent episomal
fragments of DNA that are excised during T cell receptor
gene rearrangement
VIII. Cellular tropism for HIV: role of co-receptors
 HIV-1 utilizes two major co-receptors along with CD4 to bind
to, fuse with and enter target cells
1. CCR5
2. CXCR4
 R5 viruses: strains of HIV that utilize CCR5 (or non-
syncitium inducing viruses)
 X4 viruses: strains that utilize CXCR4 (syncitium inducing
viruses)
 The mechanism of inhibition of viral entry is a steric inhibition
of binding that is dependent on signal transduction
 Transmitting virus: R5
 Progression of HIV: X4 virus or sometimes the R5 virus
IX. Cellular targets of HIV
 virtually any cell that expresses the CD4 molecule together
with co-receptor molecules can potentially be infected with
HIV
X. Abnormalities of Mononuclear Cells
A. CD4+ T cells
• One of the first abnormalities is a defect in response to
remote recall antigens such as tetanus toxoid and
influenza, at a time when mononuclear cells can still
respond normally to mitogenic stimulation
• Abnormalities include
1. defective t-cell cloning and colony-forming
efficiencies
2. impaired expression of IL-2 receptors
3. defective IL-2 production
4. decreased IFN-γ production
5. CD28 (a major co-stimulatory molecule for normal
activation of T cells) is reduced
6. low CD40 ligand
• CD4+ T cell dysfunction results from a combination of
depletion of cells due to direct infection of the cell and a
number of virus related but indirect effects on the cell
1. aberrant activation due to cytokines
2. direct effect of virus on the cell
• mechanisms of cytopathicity
1. budding of virions from cell surface
2. disruption of cell membrane
3. disruption in RNA processes
4. disruption of protein synthesis
5. accumulation of unintegrated viral DNA in
cytoplasm
6. aberrant protein tyrosine phosphorylation
• syncitia formation: involves fusion of the cell membrane
of an infected cell with the cell membranes of variable
numbers of unifected CD4+ cells
• Mechanisms of CD4+ T cell dysfunction and depletion
1. direct mechanisms
- loss of plasma membrane integrity due to
viral budding
- accumulation of unintegrated viral DNA
- interference with cellular RNA processing
- intracellular gp120-CD4 autofusion events
- syncitia formation
2. indirect mechanisms
- aberrant intracellular signaling events
- autoimmunity
- innocent bystander killing of viral antigen-
coated cells
- apoptosis
- inhibition of lymphopoiesis
- activation-induced cell death
- elimination of HIV-infected cells by virus-
specific immune responses
• inability of the immune system to regenerate the rapidly
turning over CD4+ T cell pool efficiently enough to
compensate for the loss of CD4+ T cells
B. CD8+ T cells
• These cells assume an abnormal phenotype
characterized by expression of activation markers
• Nonprogressors can be distinguished from progressors
by the maintenance in the former of a high proliferative
capacity of their HIV-specific CD8+ T cells
C. B Cells
• The predominant defect in B cells is one of aberrant
cellular activation
o Spontaneous proliferation and immunoglobulin
secretion
o Increased spontaneous secretion of TNF-α and IL-
6
• Decreased capacity to respond to ligation of the B cell
antigen receptor
• Enhanced transformation with EBV  increased
incidence of EBV-related B cell lymphomas
D. Monocyte/Macrophages
• May play a role in dissemination of HIV in the body
• Can serve as reservoirs of HIV infection
E. Dendritic and Langerhans cells
• Site of initial binding of HIV infection
• Environment for virus replication
F. Natural Killer Cells
• Abnormalities in the NK cells are due to defect in
postbinding lysis
• Decrease in activating receptors and an increase in
inhibitory receptors on NK cells
XI. Genetic Factors in HIV pathogenesis
 HLA heterozygosity for class I loci  delayed onset of AIDS
 due to presence of high variety of antigenic peptides,
compared to homozygous people
 HLA Homozygosity for class I loci  rapid progression of
AIDS
 Potential role of NK cells in maintenance of the viral set point
 Genetic mutations may affect the replication of HIV
NEUROPATHOGENESIS – neurologic abnormalities
• either due to:
1) opportunistic infections and neoplasms
2) direct effects of HIV or its product
• demonstrated in the brain and CSF with and without
neuropsychiatric abnormalities
• main cell types infected in the brain are:
1) perivascular macrophages and microglial cells
2) monocytes – infected in the blood that can migrate into the
brain where they reside as macrophages
3) macrophages – directly infected within the brain
• mechanism whereby HIV enters the brain are unclear
 ability of virus-infected and immune activated macrophages to
induce adhesion molecules such as E-selectin and vascular cell
adhesion molecule-1 (VCAM-1) on brain endothelium
 HIV gp120 enhance the expression of intercellular adhesion
molecule-1 (ICAM-1) in glial cells = facilitates entry of HIV-infected
cells into the CNS and promote syncytia formation
• virus isolated from the brain are preferentially R5 strains as
opposed to X4 strains
• HIV-infected are heterozygous for CCR5-delta32 is protected
against the development of HIV encephalopathy compared
to wild type individuals
• Distinct HIV envelope sequence are associated with the
clinical expression of AIDS demential complex
• HIV individuals manifest with white matter lesions as well as
neuronal loss
• HIV indirect pathways whereby viral proteins gp120 and Tat
trigger release of endogenous neurotoxins from
macrophages and to a lesser extent from astrocytes
• HIV-1 Nef and Tat induce chemotaxis of leukocytes,
including monocytes, into the CNS
• Neurotoxins can be released from monocytes as a
consequence of infection and/or immune activation
• Monocytes derives neurotoxic factors kill neurons via N-,
ethyl-D-aspartate receptor (NMDA)
• Gp120 shed by virus-infected monocyte could cause
neurotoxicity by antagonizing the function of vasoactive
intestinal peptide (VIP) by elevating intracellular Ca levels
and decrease nerve growth factor level in cerebral cortex
 • Monocyte-derived cytokines directly or indirectly contribute
to the neurotoxic effects: TNF-alpha, IL-1, IL-6, TGF-Beta,
IFN-gamma, platelet activating factor, endothelium
• CC-chemokines: elevated monocyte chemotactic protein
(MCP) in brain and CSF = presence and degree of HIV
encephalopathy
• Infection and/or activation of monocyte-lineage cells =
increase productions of eicosanoids, nitric oxide, and
quinolinic acid = neurotoxicity
• Astrocytes – neuopathogenesis
• TNF-alpha and IL-6 – induce atrocyte proliferation
• HIV infected with E3 allele for apolipoprotein E are at
increased risk for AIDS encephalopathy and peripheral
neuropathy
SOLUTION: ANTIRETROVIRAL THERAPY
PATHOGENESIS OF KAPOSI’S SARCOMA
4 distinct epidemiologic forms of KS:
1) classic: older men, Mediterranean or Easter European Jewish Black
wit no recognized contributing factor
2) equatorial African, all ages, no recognized precipitating factor
3) organ transplantation, immunosuppressed state
4) HIV-1 infection
#3 and #4 – KS is opportunistic disease
 HIV infected, not strictly related to depression of CD4+Tcell counts
 Pathogenesis of KS is complex
• it is an angioproliferative disease not true neoplastic
sarcoma
• excessive proliferation of spindle cells that are to be vascular
and have common features with endothelial and smooth-
muscle cells
• HIV: KS is dependent on factors:
- HIV-1 itself
- Human herpes virus 8 (HHV-8)
- Immune activation
- Cytokine secretion
 HHV-8 = Kaposi’s sarcoma-associated herpes virus (KSHV)
• it is a gama-herpesvirus related to EBV and herpes virus
saimiri
• encodes a homologue to human IL-6 and resides in the body
cavity lymphoma, multiple myeloma, and monoclonal
gammopathy of undetermined significance
• patients with KS are all seropositive for HHV-8
• HHV-8 DNA sequence can be mostly found in B cells with
KS and others without KS
• Possesses a number of genes including homologues of IL-8
receptor, Bcl-2, and cyclin D that can transform the host cell
• ETIOLOGIC AGENT OF THE DISEASE
The initiation/propagation of KS requires activated state and is
mediated by cytokines
• factors include:
- TNF-alpha, IL-1beta, IL-6, GM-CSF, basic fibroblast growth
factor, oncostatin M
- These factors function in an autocrine and paracrine manner
to sustain the growth and chemotaxis of KS spindle cells
• KSHV-derived IL-6 induced proliferation of lymphoma cells
and inhibit cytotastic effect of INF-alpha on KSHV lymphoma
cells
• IFN-gamma induce endothelial cells to proliferate and invade
the extracellular matrix in response to HIV Tat
• HIV protease inhibitors have potent anti-angiogenic
properties and promote regression of KS
IMMUNE RESPONSE TO HIV
• humoral and cell-mediated immunity
• directed against multiple antigenic determinants of HIV virion
and viral proteins expressed on the surface of infected cells
• CD4+Tcells with T cell receptors specific for HIV are the
CD4+Tcells that will bind to infected cells and be infected
and destroyed
• Early consequence of HIV infection may be interference with
generation of an effective immune response through the
elimination or compromised of HIV-specific CD4+T
lymphocytes
A. HUMORAL IMMUNE RESPONSE
• antibodies to HIV appear within 6 weeks to 12 weeks for a
primary infection
• detection of antibodies form basis for diagnostic screening
• appearance of HIV-binding antibodies detected by ELISA
and western blot
• initial decrease in plasma viremia is related to appearance of
HIV-specific CD8+Tlymphocyte
• first antibodies detected are directed against structural or
gag proteins of HIV, p24 and p17, and gag precursor p55
• development of antibodies to p24 is associated with the
decrease in serum levels of free p24 antigen
• antibodies to gag proteins are followed by the appearance of
antibodies to the envelope proteins and to the products of
the pol gene
• envelop of HIV
1) outer envelop glycoprotein with molecular mass of
120kDa
2) transmembrane glycoprotein with molecular mass
of 41kDa
- these are initially synthesized as 160kDa precursor that is
cleaved by cellular proteases
• antienvelope antibodies are directed toward
1) epitope in gp41 region comprising AA579 to 613
2) hypervariable region in gp120 known as V3 loop region, with
AA303 through 338 – V3 region is major site for
development of mutations that lead to variants of HIV that
are not well recognized by immune system
• antibodies directed toward the envelope proteins of HIV
have been characterized as being
1) protective – function to neutralize HIV directly and prevent
spread of infection to additional cells and participate in
ADCC
a. neutralizing antibodies – component of primary HIV infection
and long term nonprogressors that have increased titers of
neutralizing antibodies
- appear in two forms:
I. type specific
- directed to the V3 loop region
- neutralize only viruses of given strain and are present in low
titer in most infected individuals
II. group specific
- neutralizing a wide variety of HIV isolates
- 2 forms have been identified: binding to AA423 to 437 of
gp120 and binding to AA 728 to 745 of gp41
b. participate in ADCC – form of cell mediated immunity
- NK cells that bear Fc receptors are armed with specific
antiHIV antibodies that bind to NK cells via Fc portion
- Armed NK cells then bind to and destroy cells expressing
HIV antigens
- Antibodies to both gp120 and gp41 participate in ADCC
mediated killing of HIV infected cells
- Levels of antienvelope antibodies capable of mediating
ADCC are highest in the earlier stages of HIV infection
- Il-2 can augment ADCC mediated killing
2) contributing to the pathogenesis of HIV disease
a. antibodies directed to gp41, when present in low titer have
been shown to facilitate infection of cells through an Fc
receptor-mediated mechanism known as antibody
enhancement
b. anti-gp120 antibodies that participate in ADCC killing of HIV
infected cells might kill uninfected CD4+tcells if the
uninfected cells had bound free gp120 = phenomena,
HYSTANDER KILLING
B. CELLULAR IMMUNE RESPONSE
• T-cell mediated plays a role in host defense against most
viral infections – important component of host immune
response to HIV
• T cell immunity can be divided into 2 major categories:
helper/inducer CD4+Tcell and cytotoxic/immunoregulatory
CD8+Tcell
• CD4+Tcell can be detected in majority of HIV infected
patients through the use of flow cytometry to measure cell
IFN-gama production in response to HIV antigens, binding to
MHC class II tetramers or HIVp24 lymphocyte proliferation
assays
• They have high affinity for binding to HIV infected cells may
be among the first to be infected and destroyed during HIV
infection
• Undergo clonal expansion in response to HIV antigens and
survive as a population of cells
• Several regions of HIV-1 envelope molecule have been
identified that are structurally analogous to other known T
cell epitopes by virtue of having structures known as
AMPHOPATHIC HELICES  identify presence of CD4+Tcell
• MHC class I-restricted HIV specific CD8+Tcell have been
identified
- include: CTLs and T cells to express cytokines such as IFN-
gamma
• 2 types of CTL
 1) directly lyses appropriate target cells in culture
without prior in vitro stimulation (spontaneous CTL
activity)
2) reflects the precursor frequency of CTLs (CTLp) –
demonstrated by stimulation of CD8+Tcells in vitro
with a mitogen such as phytohemagglutinin or
antiCD3 antibody
• broad CD8+CTL response generally have more favorable
clinical course that do patient who mount a more restricted
CTL response
• 3 forms of cell mediated immunity to HIV have been
described
1) CD8+Tcell mediated suppression of HIV replication
- ability of CD8+Tcell from HIV infected patient to inhibit
replication of HIV in tissue culture in a noncytolytic manner
- nonspecific and mediated by soluble factors including CC-
chemokines RANTES, MIP-1alpha, MIP1Beta and alpha
defensin family of cytokines
- CC-chemokines are potent suppressors of HIV replication
and operate at least in part via blockade of co-receptor
2) ADCC
- inhibit replication of either R5 or X4
- killing HIV expressing cells by NK cells armed with specific
antibodies directed against HIV antigen
3) NK cell activity
- kill HIV infected target cells in tissue culture
- directed toward nonspecific surveillance for neoplastic
transformation and viral infection through recognition of
altered class I MHC molecules
DIAGNOSIS AND LABORATORY MONITORING OF HIV INFECTION
• blood donors screened for antibodies to HIV
• p24 antigen capture assay to screen process to help identify
the rare infected individuals who were donating blood in the
time of 3 months between infection and the development of
antibodies
• ability to detect early infection with HIV further enhanced by
nucleic acid amplification testing as a routine part of blood
donor screening
• 22 days for antibody testing, 16 days for p24 antigen testing
and 12 days for nucleic acid testing
• sensitive assays help monitor level of plasma viremia
ushered in new era of being able to monitor the progress of
HIV disease more closely
• tests measure level of CD4+ in peripheral blood for
management of patients with HIV infection
A. DIAGNOSIS OF HIV INFECTION
• standard screening: ELISA
- enzyme immunoassay (EIA)
- solid-phase assay good screening test with sensitivity of
>99.5%
- use commercial EIA kit with antigens from both HIV-1 and
HIV-2
- use natural and recombinant antigens and are updated to
increase their sensitivity to newly discovered species such
as group O viruses
- scored as positive (highly reactive)
negative (nonreactive)
indeterminate (partially reactive)
- not specific
- false positive: antibodies to class II antigens, autoantibodies,
hepatic disease, recent influenza vaccine, acute viral
infection
- confirm with specific assay
• confirmatory test: WESTERN BLOT
- specific
- demonstrate antibody to products of all three major genes of
HIV (gag, pol, env)
- positive if antibodies exist to 2 of the 3 HIV proteins: p24,
gp41, gp120/160
- test repeated 1 month to determine indeterminate pattern is
a pattern in evolution
- excellent confirmatory test with HIV infection of a positive or
indeterminate EIA
- poor screening test
- reactivity that do not fall into the positive/negative categories
are “indeterminate”
 2 possible explanations for indeterminate western blot
1) low risk individual tested has antibodies that cross react with
one of the proteins of HIV
2) individual is infected with HIV and is in the process of
mounting a classic antibody response
REFER TO PAGE 1101 FOR THE ALGORITHM OF USING
SEROLOGIC TESTS
• p24 antigen capture assay – simplest of direct detection
tests
- EIA type assay in which solid phase consists of antibodies to
the p24 antigen of HIV
- Detects the viral protein p24 in blood if HIV individual
- Free antigen or complexed to anti-p24 antibodies
- Untreated HIV infection have detectable levels of free p24
antigen
- First few weeks of infection before immune response
develops there is a brisk rise in p24 antigen
- After development of anti-p24 antibodies, levels decline
- Late in course of infection, circulating level of virus are high,
p24 antigen levels also increase when detected by
techniques involving dissociating of antigen-antibody
complexes
- Use of p24 assay has been replaced by the use of nucleic
assay testing  DNA PCR = amplify HIV proviral DNA from
peripheral blood mononuclear cells
• consequence of high degree sensitivity is loss of specificity
and false positive results have been reported with each
technique
- positive EIA with confirmatory of western blot is the GOLD
STANDARD
• RT-PCR following DNase treatment, a CDNA copy
- cDNA copy is made of all RNA species present in plasma
- bDNA assay involves the use of solid-phase nucleic acid
capture system and signal amplification through successive
nucleic acid hybridization to detect small quantities of HIV
RNA
LABORATORY MONITORING OF PATIENTS WITH HIV INFECTION
*** Both predict prognostic information
• CD4+ T cell counts provide information on the current
immunologic status of patient
• HIV RNA level predicts what will happen to CD4+ T cells
count in near future
CD4+TCELL
• best indicator of immediate state of immunologic
competence of patient with HIV infection
• product of percent CD4 and total lymphocyte count
• level of immunologic competence
- <200ul high risk of infection with P.carinii
- <50ul infection with CMV and mycobacterium of M.avium
complex
• monitor every 3 to 6 months
• <350ul = antiretroviral therapy
• >25% = change in therapy
• <200ul = placed on P.carinii prophylaxis
• <50ul = prophylaxis for MAC infection
HV RNA DETERMINANTS
• monitor patient with HIV infection
• RT-PCR assay and bDNA assay
• Monitor every 3 to 4 months with untreated patients
• >50,000 = therapy
• proven, monitor every 4 weeks
• effective therapy if <50 copies, achieved within 6 months of
therapy
HIV RESISTANCE TESTING
• either genotypic or phenotypic measurements
1) genotypic
- sequence analyses of HIV genomes obtained from patients
are compared to sequences of viruses with known
antiretroviral resistance profiles
2) phenotypic
- vivo growth of viral isolates obtained from the patient are
compared to the growth of reference strains of the virus in
the presence or absence of different antiretroviral drugs
OTHER TESTS
• quantitative culture of replication-competent HIV from
plasma, peripheral blood mononuclear cells or resting CD4
circulating levels of B2 microglobulin, soluble IL-2 receptor,
IgA, acid labile endogenous interferon, or TNF-alpha and the
presence of absence of activation markers such as CD38 or
HLA-DR on CD8
CLINICAL MANIFESTATION
A. ACUTE HIV SYNDROME
• acute clinical syndrome
• 3 to 6 weeks after primary infection
• fever, skin rash, pharyngitis, myalgia
• acute infection mononucleosis
• 1 to several weeks
 • subside as immune response to HIV develops and levels of • organ infection associated with cystic lesions that may
plasma viremia decrease appear calcified on CT or US
• number of total lymphocytes and T cell subsets (CD4 and • standard treatment for PCP or disseminated pneumocytosis
CD8) are initially reduced is trimethoprim/sulfamethoxazole (TMP/SMX)
• inversion of CD4/CD8 ratio occur later because of a rise in - side effects: skin rash, bone marrow suppression
number of CD8 - mild to moderate: : dapsone/trimethoprim and clindamycin
• total circulating CD8 are elevated or return to normal - IV pentamidine for severe or unable to tolerate TMP/SMX
• CD4 are depressed or normal - Glucocorticoid to correct ABG
- 21 day treatment with secondary prophylaxis
B. ASYMTPOMATIC – CLINICAL LATENCY - indicated
1) patient with CD4<200ul
• untreated patients – 10 years
2) CD4<15%
• patients with high levels of HIV RNA in plasma progress to 3) Fever >2 weeks
symptomatic disease faster than do patient with low levels of 4) Any patient with Hx of oropharyngeal candidiasis
HIV RNA • preferred regimen for prophylaxis is TMP/SMX = protection
• patients referred to as long term nonprogressors show little also against toxoplasmosis and some bacterial respiratory
of any decline in CD4 cell counts over extended periods of pathogen
time
• extremely low levels of HIV RNA • M.tuberculosis
• entirely asymptomatic despite the fact that CD4 show steady - >5mm
progressive decline to exceed extremely low levels - treat 9 months with isoniazid
• asymptomatic period: average rate of CD4 decline is 50ul - most common atypical mycobacterium infection is with
• CD4 fall <200ul = immunodeficiency is severe enough to M.avium or M.intracellular species (MAC)
place patient at high risk for opportunistic infection and - MAC infection <50ul = fever, weight loss, nigh sweats
neoplasm - Diagnosis is culture of blood or involved tissue  2
consecutive sputum samples +
C. SYMPTOMATIC DISEASE - Therapy: macrolide, clarithromycin with ethambutol
• <200ul
• indicator: • Rhodococcus equi – gram + pleomorphic acid-fast nonspore
1) diagnosis of AIDS with HIV infection CD4 <200ul forming bacillus that can cause pulmonary and disseminated
2) HIV infection with on of HIV associated diseases infection in patient with HIV infection
• secondary infection with opportunistic organisms – P.carinii, - fever cough
atypical mycobacterium, CMV, others - cavitary lesion and consolidation
- blood culture +

DISEASE OF THE RESPIRATORY SYSTEM • Fungal infection – lung

- cryptococcal
• acute bronchitis and sinusitis present in all stages - fever, cough, dyspnea, hemoptysis
• severe cases: low CD4 - focal or diffused interstitial infiltrate
• sinusitis – fever, nasal congestion, headache - lobar disease, cavitary, pleural effusion, hilar or mediastinal
• diagnosis made by CT or MRI adenopathy
• maxillary sinus most commonly involved
• coccidiodes immitis – mold
• improve without antibiotic therapy, radiographic improvement
- reactivation pulmonary syndrome
is quicker - CD4<250ul
• increased frequency of infection with encapsulated - Fever, weight loss, cough
organisms such as H. influenza and S. pneumonia
• low CD4 = macromycosis of sinuses • Aspergillus infection
• local debridement and systemic amphoterecin B may be - pseudomembranous tracheobronchitis
needed for effective treatment
• Pulmonary disease is frequent complication HIV infection • primary pulmonary infection of the lung may be with
- most common manifestation: pneumonia HISTOPLASMOSIS
- 2 most common causes of pneumonia - disseminated disease
1) bacterial infection
2) P. carinii • idiopathic interstitial pneumonia
• other major causes of pulmonary infiltrates: myocobacterial 1) lymphoid interstitial pneumonitis – common in children,
infection, fungal infection, nonspecific interstitial benign infiltrate
pneumonitis, KS, lymphoma 2) nonspecific interstitial pneumonitis
• encapsulated S.penumoniae, H.influenza
• consequence of altered B cell function and defect in • neoplastic disease of the lung: KS, lymphoma
neutrophil function
• pneumococcal infection may be the earliest serious infection
• pneumonia, sinusitis, bacterimia continuation: disease of respiratory system p1108
• CD4-300ul = inflammatory response  proportional to CD4 Rhodococcus equi
cell  g(+) pleomorphic acid-fast non-sporeforming bacillus
- immunization with pneumococcal polysaccharide  pulmonary &/or disseminated infx in px w/ HIV
• P.carinii, old hallmark of AIDS  fever & cough are the most common presenting signs
- decline in incidence because of prophylactic regimens and
combination antiretroviral therapy Coccidiodes immitis
- single most common cause of pneumonia in HIV  mold; endemic in SW US
- recurrent fever, night sweats, unexplained weight loss
 can cause reactivation pulmonary syndrome in px w/ HIV
- PCP present with fever and cough, nonproductive, white
sputum  CD4+ T cell counts <250 uL
- Retrosternal chest pain, worse on inspiration, sharp or  fever, wt loss, cough, & extensive, diffuse reticuloodular
burning infiltrates on chest X-ray
- Chest x-ray: normal, faint bilateral interstitial infiltrate, dense
perihilar infiltrate Aspergillosis
- Aerosolized pentamidine: upper lobe cavity, like TB  not AIDS defining
• Mild leukocytosis  generally not seen in px with AIDS in the absence of
- ABG has hypoxemia neutropenia or administration of glucocorticiods
• Otic involvement  pseudomembranous tracheobroncholitis
- polyploidy mass involving external auditory canal
Histoplasmosis
• ophthalmic lesion of choroids, necrotizing vasculitis that
 most common in disseminated disease due to reactivation
resembles Burger’s disease, bone marrow hypoplasia,
intestinal obstruction  minimal respiratory symptoms (cough & dyspnea)
• lymph nodes, spleen, liver, kidney, pancreas, pericardium,  diffuse interstitial infiltrate or diffuse small nodules
heart, thyroid, adrenals
Idiopathic interstitial pneumonia
1. lymphoid interstitial pneumonitis (LIP)
 2. nonspecific interstitial pneumonitis (NIP)
LIP
 common finding in children; 1% adult w/ HIV
 charac: benign infiltrate of the lung, part of polyclonal activation of
lymphocytes in HIV & EBV infxs
 dx: transbronchial biopsy (50%); open lung biopsy
 self-limited & no specific tx necessary
NIP
 ½ of untreated HIV px
 interstitial infiltrates of lymphocytes & plasma cells in
perivascular & peribronchial distribution
 fever, unproductive cough, mild chest discomfort
 faint interstitial pattern in CXR
 self-limited & no specific tx necessary
Neoplastic diseases
 KS, Lymphoma
Esophagitis
 present with odynophagia and retrosternal pain
 may be due to Candida, CMV, or HSV
 CMV-single large ulcer
 HSV- multiple small ulcer
 respond to Thalidomide
Achloridia
 common problem in HIV
Infections of the Small and Large Intestine
 leading to diarrhea, abdominal pain, and occasional fever are
among the significant GIT problems in HIV patients
 Salmonella, Shigella, and Camylobacter are most common in
homosexual men and are often more severe and apt to relapse
 S. typhi murium- 20 fold increase in HIV patients
 dx: culture and blood stool
 tx: long term therapy with Ciprofloxacin

DISEASES OF CARDIOVASCULAR SYSTEM Campylobacter jejuni

1. direct consequence of HIV infx  strain most frequently isolated
2. consequence of antiretroviral therapy (Lipodystrophy  crampy abdominal pain, fever, and bloody diarrhea
Syndrome)  may present as proctitis
 stool exam: fecal leukocytes
HIV-associated Cardiomyopathy
 tx: erythromycin
 primary consequence of HIV infx
 dilated cardiomyopathy associated w/ CHF Histoplamosis, Coccidioidomycosis, Peniciliosis
 most common clinically significant finding  fever and diarrhea
 late complication of HIV
 advocated tx w/ Ig Cryptosporidia, Microsporidia, and Isospora belli
 most common opportunistic protozoa in GIT and cause
Cardiomyopathy diarrhea in HIV patients
 may be due to side effectof IFN-alpha nucleoside analogue
therapy, reversible when stopped Cryptosporidial infection
 may be due to KS, cryptococcus, Chagas disease, or  CD4+T cell counts <300 / μL
toxoplasmosis (MRI or double-dose contrast CT scan for CNS  diarrhea, crampy abdominal pain, N/V
toxoplasmosis in any px w/ advanced HIV & cardiomyopathy)  may also cause biliary tract disease leading to cholecystitis
 non-inflammatory diarrhea, oocysts that stain with acid fast
Pericardial Effusions dyes
 in advanced HIV
 predisposing factors: TB CHF, mycobacterial infx, ryptococcal  tx: nitazoxanide - improves symptoms, decrease shedding of
infx, pulmonary infx, cryptococcal infx, lymphoma, & KS organisms; supportive; anti-retroviral therapy
 avoid contact with human and animal feces; not drinking
Pericarditis untreated water
 Nonbacterial thrombotic endocarditis – px w/ unexplained
thrombotic phenomena Microsporidia
 Rapidly infused pentamidine – can result to hypotention as a  small, unicellular, obligate intracellular parasite
consequence of cardiovascular collapse  reside in cytoplasm of enteric cells
 HAART side effect – hypertriglyceridemia, elevations of
cholesterol, & CAD; 25% increase risk of myocardial infarction Enterocytozoo bieneusi- main species causing disease in humans
 dx: electron microscopy
DISEASES OF OROPHARYNX & GASTROINTESTINAL SYSTEM  extra-intestinal locations (eye, muscle, liver)
→ common features on HIV  conjuctivitis, hepatitis
→ most frequently due to secondary infections  tx: albendazole
→ also occur in KS & lymphoma
→ Thrush (Candida) & oral hairy leukoplakia (EBV) are usually I. belli
indicative of fairly advanced immunologic decline, CD4+ T cell  most commonly found as cause of diarrhea in patients in
counts <300 /uL Caribbean and Africa
 easy to treat with TMP/SMX
Thrush  CMV colitis
 appears as a white cheesy exudates, often on an  now less common with advent with HAART
erythematous mucosa in the posterior oropharynx  abdominal pain, weight loss, anorexia, non-bloody diarrhea
 most commonly seen in the soft palate  tx: gancyclovir or foscarnet
 early lesions along the gingival border  monitor for retinitis
 dx: direct examination of scarping for pseudohyphal elements;
culture has no dx value AIDS Enteropathy / HIV Enteropathy
 chronic diarrheal syndrome for which no other etiologic other
Oral Hairy Leukoplakia than HIV can be identified
 white, fond like lesions, generally along the lateral borders of  direct result of HIV infx in the GIT
the tongue, & sometimes on the adjacent buccal mucosa  decrease or absence small bowel lactase and malabsorption
 not considered a premalignant accompanying weight loss
 lesions associated w/ florid replication of EBV  if non-revealing dx evaluations, diarrhea for greater than 1
 usually a more disconcerting sign of HIV-associated month
immunodeficiency
 tx: topical podophyllin; systemic therapy w/ anti-herpes agents Rectal Lesions
 perirectal ulcer and erosions due to reactivation of HSV
Aphthous Ulcers  tx: acyclovir, famciclovir, or foscarnet
 posterior oropharynx
 regularly seen in px w/ HIV infx HEPATOBILIARY DISEASE
 unknown etiology → major problem, one-third of deaths of patients with HIV
 quite painful & interfere w/ swallowing
 tx: topical anesthetic; Thalidomide (pathogenesis may involve HBV
tissue-destructive cytokines)  95% of HIV patients with HBV
 patients with both HBV and HIV have decreased inflammatory
Palatal, Glossal, or Gingival Ulcers liver disease (immunosuppressive effects of HIV)
 may result from cryptococcal disease or histoplasmosis  more severe hepatitis following initiation of effective retroviral
therapy
 tx: lamivudin or adefovir/ tenofovir
  may also be due to adrenal insufficiency
HCV
 more severe in patients with HIV Thyroid function
 increased rate of cirrhosis  generally normal 2-3% may have elevations in TSH
 tx: pegylated IFN-alpha (two-log drop in HSCV RNA within 12  opportunistic infection in advanced HIV disease
weeks)  nontender diffuse enlargement of the thyroid gland but thyroid
function is usually normal
Hepatitis G Virus  dx: FNAB
 GB virus C
 50% of patients with HIV Hypogonadism
 decreased rate of progression to AIDS  in 50% of men
 testicular disfcn- gancyclovir therapy
Nucleoside Analogues  2/3 of patients- decreased libido, 1/3 of patients complain of
 inhibit DNA synthesis impotence
 toxic to mitochondria, disturbance in oxidative metabolism  tx: androgen replacement therapy – considered in patients with
 manifests as hepatic steatosis, lactic acidosis and fulminant hypogonadism
liver failure  no significant effect on menstrual cycle unless advanced
 reversible if discontinued early disease

Nevirapine RHEUMATOLOGIC DISEASES

 fatal fulminant and cholestatic hepatitis, hepatic necrosis and
hepatic failure
Indianvir
 mild to moderate elevations in serum bilirubin
HAART
 unexplained increase in hepatic trans-aminase
Pancreatic injury
 most commonly as a consequence of drug toxicity
 secondary to pentamidine or dideoxynucleoside
DISEASES OF THE KIDNEY AND GENITOURINARY TRACT
Immune Reactivation Syndromes
 a variety of exaggerated immune responses to existing
opportunistic infxs following initiation of antiretroviral therapy
Drug Allergies
 the most significant allergic reactions occurring in HIV-infected
patients
 TMP/SMX – erythematous, morbilliform eruptions that are
pruritic, tend to coalesce, occur w/ fever
 these reactions are not an immediate indication to stop the
drug
 Nucleoside Analogue Abacavir – fatal hypersensitivity
reactions, absolute contraindication to future therapy

HIV- associated Nephropathy Autoimmune Diseases

 leading cause of ESRD in patients with HIV → substantial polyclonal B cell activation
 direct complication of HIV → associated w/ high incidence of antiphospholipid antibodies
 can be an early manifestation of HIV infection also seen in → despite serologic findings, there is no evidence that HIV-infected
children individuals have an increase in incidence of SLE nor RA
 proteinuria - hallmark
 focal, segmental glomerulosclerosis (80%), and mesangial Diffuse Infiltrative Lymphocytosis Syndrome (DILS)
proliferation  may occur in increase frequency in patients w/ HIV infx
 tx: prednisone  a variant of Sjogren’s syndrome
 syndrome consisting of parotid gland enlargement, dry eyes,
T. pallidum and dry mouth
 etiologic agent of syphilis  associated w/ lymphocytic infiltrates of the salivary gland &
 important role in HIV epidemic lung
 in HIV negative individuals, genital syphilic ulcers as well as  Sjogran’s Syndrome – infiltrates are composed predominantly
ulcers of chancroid are major predisposing factors of of CD4+ T cells
heterosexual transmission of HIV infx  HIV – predominantly CD8+ T cells
 lues maligna – ulcerating lesions of the skin due to necrotizing
vasculitis Reactive Athritides
 condylomata lata – a form of secondary syphilis  HIV px generally respond to standard tx
 neurosyphilis – 1% in patients with HIV  therapy w/ Methotrexate has been associated w/ increase
 dx: VDRL test, anti-FTA test, dark field examination opportunistic infx
 false positive VDRL tests due to polyclonal B cell
HIV or AIDS-Associated Arthropathy
Vulvovaginal Candidiasis  HIV-infected individuals also experience a variety of joint
 common problem in women with HIV problems w/o obvious cause
 pruritis, discomfort, dyspareunia and dysuria  this syndrome is characterized by subacute oligoarticular
 pseudohyphal elements in 10% KOH arthritis developing over a period of 1 to 6 weeks and lasting 6
 tx: topical therapy; fluconazole weeks to 6 months tx: intraarticular glucocorticoids

DISEASES OF THE ENDOCRINE SYSTEM AND METABOLIC Painful Articular Syndrome

DISORDERS
Lipodystrophy
 elevations in plasma TGAs, total cholesterol and apo-
lipoproteins B, hyperinsulinemia, and hyperglycemia
 truncal obesity – increase in mesenteric fat, dorso-cervical fat
pad (buffalo hump)
 enlargement of breast, prominence of veins in the legs
 associated with protease inhibitor therapy, potent protease
sparing therapy, thymidine analogues
 gemfibrozil, atorvastatin – most commonly utilized agents in
this setting
 HAART – osteonecrosis or avascular necrosis of the hip and
shoulders
 lipid lowering agents, systemic glucocorticoids, testosterone,
anti-cardiolipin abs, body-building exercises – can cause
osteonecrosis
 nucleoside reverse transcriptase inhibitors – lactic acidosis
SIADH
 hyponatremia
 as a consequence of increased free water intake and
decreased free water excretion
 thought to be secondary to HIV infx
 presents as an acute, severe, sharp pain in the affected joint
 affects primarily the knees, elbows, and shoulder
 lasts 2- 24 hrs.
Fibromyalgia
 widespread musculoskeletal pain of at least 3 months duration
and the presence of at least 11 of 18 possible tender points by
digital palpation
 direct result of HIV infx
Septic arthritis
 rare
 due to systemic fungal infection w/ C. neoformans, Sporothrix
schenckii, or H. capsulatum, or to systemic mycobacterial
infection
Immune Reactivation Syndromes
 paradoxical worsening of preexisting, untreated, or partially
treated opportunistic infections
 may be noted following the initiation of antiretroviral therapy
 common in patients w/ underlying mycobacterial infxs
 similar to type IV hypersensitivity reactions
  reflect the immediate improvements in immune function that
occur as levels of HIV RNA drop and the immunosuppressive
effects of HIV infx are controlled
 tx: glucocorticoids may be used to blunt the effect
DISEASES OF THE HEMATOPOIETIC SYSTEM
→ direct histologic examination and culture of lymph node or bone
marrow tissue are often diagnostic
→ initiation of HAART will lead to reversal of most hematologic
complications that are the direct effect of HIV infx
Persistent Generalized Lymphdenopathy
 presence of enlarged lymph nodes (>1cm) in 2 or more
extrainguinal sites for > 3 months w/o an obvious
 cause
 the lymphadenopathy is due to marked follicular hyperplasia in
the node in response to HIV infx
 not associated / the likelihood of developing AIDS
 in patients w/ CD4+ T cell counts >200/uL, ddx are KS, TB, &
lymphoma
 lymph node biopsy usually indicated in CD4+ T cell counts <
200/uL
Anemia
 the most common hematologic abnormality in HIV infected
patients
 Zidovudine – may block erythroid maturation prior to its effects
on other bone marrow elements; characteristic feature:
elevated MCV
 Dapsone – can cause serious hemolytic anemia in patient
deficient of glucose-6-phosphate dehydrogenase; can create
functional anemia in others through induction of
methemoglobinemia
Neutropenia
 puts the patient at risk of spontaneous bacterial infxs
 most frequently seen in patients w/ severe advanced HIV
Thrombocytopenia
 maybe an early consequence of HIV infx
 CD4+ T cell counts <400/uL have high risk of platelet counts <
150,000/uL
 clinically resembles thrombocytopenia seen in px w/ idiopathic
thombocytopenic purpuras
 most effective medical tx: HAART
 if <20,000/uL: intravenous Ig or anti-Rh Ig / anti-retroviral
therapy
 Splenectomy: Pnemococcal polysaccharide vaccine is
required; unreliable CD4+ T cell counts; use CD4+ T cell
percent; CD4+ T cell percent of 15 is approximately equivalent
to CD4+ T cell count of 200/uL
Classic Thrombocytic Thrombocytopenia Purpura
 clinical syndrome consisting of fever, thrombocytopenia,
hemolytic anemia, & neurologic & renal dysfunction
 rare
 tx: Salicylates & Plasma Exchange
DERMATOLOGIC DISEASES
→ >90% of px w/ HIV infx
Seborrheic Dermatitis
 50% of px w/ HIV infx
 increases severity as the CD4+ T cell count declines
 tx: antifungal agents if refractory to standard topical tx
Eosinophilic Pustular Folliculitis
 rare
 increased frequency in HIV px
 multiple, urticarial perifollicular papules that may coalase into
plaquelike lesions
 biopsy: eosinophilic infiltrate of the hair follicle
 may be associated w/ a mite
Psoriasis & Ichthyosis
 more refractory to tx in the setting of HIV
 not reported to be increased in frequency
Reactivation Herpes Zoster ( Shingles)
 reactivation syndrome of varicella-zoster virus indicates a
modest decline in immune function and may be the first
indication of clinical immunodeficiency
 AIDS was more likely to develop if the outbreak of zoster was
associated w/ severe pain, extensive skin involvement, or
involvement of cranial or cervical dermatomes
 tx: Acyclovir or Famciclovir
Molluscum contagiosum
 flesh colored umbilicated lesions
 may be treated w/ local therapy tend to regress w/ effective
anti retroviral therapy
Drug Reactions
 erythroderma
 Stevens-Johnson Syndrome – reaction to sulfa drugs, the
nonnucleoside reverse transcriptase inhibitors, abacavir and
amprenavir
Zidovudine
 elongation of eyelashes development o a bluish discoloration
to the nails
 more in African-American
Clofazimine
 yellow-orange discoloration of the skin
NEUROLOGIC DISEASES
→ secondary diseases of CNS occur in approximaely1/3 of px w/
AIDS
→ frequency is considerably less in pxs receiving effective
antiretroviral drugs
→ neurologic problems occur throughout the course of disease
and may be inflammatory, demyelinating, or degenerative in
nature
→ AIDS dementia complex / HIV encephalopahy – only 1
considered as AIDS defining illness
→ damage to the CNS may be a direct result of viral infx of the
CNS macrophages or glial cells or may be secondary to the
release of neurotoxins and potentially toxic cytokines
→ E4 allele for apolipoprotein E – increases the risk for AIDS
encephalopathy and peripheral neuropathy
→ virtually all patients w/ HIV infection have some degree of
nervous system involvement w/ the virus
→ It is important to point out that evidence of infx of the CNS w/
HIV does not imply impairment of cognitive function neurologic
function of an HIV-infected individuals should be considered
normal unless clinical signs and symptoms suggest otherwise
Aseptic Meningitis
 very late stages of HIV infx
 a syndrome of headache, photophobia, and meningismus
 cranial nerve involvement may be seen (CN VII but
occasionally V/ VIII)
 CSF findings include lymphocytic pleocytosis, elevated protein
level, and normal glucose
 cannot be clinically differentiated from other viral meningitides
 resolves spontaneously within 2-4 weeks
 clinical aseptic meningitis in the context of HIV infx is an
immune-mediated disease
C. neoformans
 leading cause of meningitis in patients w/ AIDS
 initial AIDS-defining illness in 2% of patients
 generally occurs in patients with CD4+ T cell counts<100/uL
 fever, nausea, vomiting, altered mental status, headache, and
meningeal signs
 CSF profile may be normal or may show only modest elevation
of WBC or protein levels
 1/3 of patients have pulmonary disease
 the prostate gland may serve as reservoir for smoldering
Cryptococcal infx
 dx: India ink examination or detection of Cryptococcal antigen
in CSF
 tx: IV amphotericin V with flucytosine followed by fluconazole
until CD4+ T cell count has increased to >200/uL for 6 months
in response to HAART
 symptoms may recur with initiation of HAART as an immune
reconstitution syndrome
 other fungi that may cause meningitis in patients with HIV infx
are C. immitidis, H. capsulatum
HIV Encephalopathy/ HIV-associated Dementia
 constellation of signs and symptoms of CNS disease
 generally, a late complication of HIV infx that progresses slowly
over months
 it can be seen in patients with CD4 counts >350 cells /ul
 a major feature is development of dementia
 aphasia, apraxia, and agnosia are uncommon in contrast to
cortical dementia; subcortical dementia
 motor and behavioral abnormalities
 late stages may be complicated by bowel and/ bladder
incontinence
 these changes usually occur w/o significant changes in level of
alertness
 initial AIDS-defining illness in 3% of patients with HIV; this only
rarely precedes clinical evidence
  direct effects of HIV on CNS
 multi-nucleated giant cells, macrophages, and microglial cells
appear to be the main cell types harboring virus in the CNS
 there are no specific for dx of HIV encephalopathy
 this syndrome must be differentiated from a number of other
diseases that affect the CNS of HIV-infx patients
 Lumbar puncture - important element in the evaluation of
patients with HIV and neurologic abnormalities; most helpful in
ruling out or making a dx of opportunistic infxs
 Seizures - threshold is lower than normal owing to the frequent
presence of electrolyte abnormalities
 Cryptococcal meningitis was the 3rd most common diagnosis
responsible for seizures
 tx: phenytoin- initial treatment of choice; hypersensitivity
reactions; phenobarbital or valproic acid- alternatives
 focal neurologic deficits – most common causes are
toxoplasmosis, PML, and CNS lyphoma
Toxoplasmosis
 one of the most common causes of secondary CNS infx in
patients w/ AIDS
 generally a late complication f HIV infx
 CD4+ T cell counts <200/uL
 screen for IgG antibodies to T. gondii during the initial workup
 most common clinical presentation of cerebral toxoplasmosis
in pxs w/ HIV infx is fever, headache, and focal neurologic
deficits
 patients may present w/ seizure, hemiparesis, or aphasia as a
manifestation of these focal deficits or w/ a picture more
influenced by the accompanying cerebral edema &
characterized by confusion, dementia, and lethargy, which can
progress to coma
 MRI: multiple lesions although in some cases only a single
lesion is seen
 ddx: primary CNS lymphoma; less commonly TB, or
fungal/bacterial abscess
 definitive dx procedure: Brain Biopsy
 Standard Tx: Sulfadiazine & Pyrimethamine w/ Leucovorin as
needed
 patients w/ CD4+ T cell counts < 100/uL and Ig G antibody to
Toxoplasma should receive primary prophylaxis for
toxoplasmosis
 Single double strength tablet or TMP/SMX used for P. carinii
prophylaxis provides adequate primary protection against
toxoplasmosis
 Secondary prophylaxis for toxoplasmosis my be discontinued
in the setting of effective antiretroviral therapy and increases in
CD4+ T cell counts to >200/uL for 6 months
Progressive Multifocal Leukoencephalopathy
 JC virus an important opportunistic pathogen in patients w/
AIDS
 PML is the only known clinical manifestation of JC virus infx
 late manifestation of AIDS
 begin as small foci of demyelination in subcortical white matter
that eventually coalesce
 have a protracted course w/ multifocal neurologic deficits w/ or
w/o changes in mental status
 MRI: multiple nonenhancing white matter lesions that may
coalesce and have a predilection for the occipital & parietal
lobes
 no specific tx for PML
Progressive Multifocal Leukoencephalopathy (PML)
- etiologic agent: JC Virus (important opportunistic pathogen of patients
with AIDS)
- only known clinical manifestation of JC virus
- late manifestation of AIDS
- seen in ~4% of patients with AIDS
- lesions begin as small foci of demyelination in subcortical white
matter that eventually coalesce
- cerebral hemispheres, cerebellum, and brainstem may all be involved
- patients typically have a protracted course with multifocal neurologic
deficits, w/ or w/o
changes in mental status
- ataxia, hemiparesis, visual field defects, aphasia and sensory defects
may occur
- MRI: multiple, nonenhancing white matter lesions that may coalesce
and have predeliction for the occipital and parietal lobes
- paradoxical worsening seen with initiation of HAART as immune
reactivation syndrome
- no specific treatment; however, regressions of >2.5 years in duration
reported in patients with PML treated with HAART for HIV disease
- factors influencing good prognosis
(1) CD4+ T cell count >100µL at baseline
(2) ability to maintain an HIV viral load of 500 copies per
milliliter
- one of the few opportunistic infections that continues to occur with
some frequency despite the widespread use of HAART
Reactivation American trypanosomiasis
- may present as acute meningoencephalitis with focal neurologic
signs, fever, headache, vomiting and seizures
- lesions appear radiographically as single or multiple hypodense areas
typically with ring enhancement and edema
- predominantly in subcortical areas (differentiates them from deeper
lesions of toxoplasmosis)
- CSF findings:
 presence Trypanosoma cruzi amastigotes or trypanosomes
 elevated protein
 mild (<100 cells/µL) lymphocytic pleocytosis
- organisms could also be identified from biopsy specimens and by
direct examination of the blood
- treatment: benzimidazole (2.5 mg/kg bid) or nifurtimox (2mg/kg qid)
for at least 60 days, followed by maintenance therapy for life with either
drug of 5mg/kg 3x a week
Stroke
- symptoms are sudden in onset
- secondary infectious diseases in patients w/ HIV infxn that may be
assoc. w/ stroke:
(1) vasculitis due to cerebral varicella zoster or neurosyphilis
(2) septic embolism in assoc. w/ fungal infxn
- differential dx: atherosclerotic cerebral vascular disease, TTP, and
cocaine or amphetamine use
Spinal cord disease or myelopathy
- in ~20% of patients with AIDS, often as part of HIV encephalopathy
- 90% patients w/ HIV-assoc. myelopathy have some evidence of
dementia
- three main types
(1) vacuolar myelopathy – pathologically similar to subacute combined
degeneration of the cord such as occurs w/ pernicious anemia
- characterized by a subacute onset and often presents w/
gait disturbances, predominantly ataxia and spasticity
- may progress to include bladder & bowel dysfunction
- increased DTRs & extensor plantar responses
(2) involves the dorsal columns and presents as a pure sensory ataxia
(3) sensory in nature and presents w/ paresthesias & dysesthesias of
the lower extremities
- do not respond well to antiretroviral drugs; therapy is
mainly supportive
Myelopathy and Polyradiculopathy in assoc. w/ CMV infxn
- one impt disease of spinal cord that involveds peripheral nerves
- generally seen late in course of HIV infxn
- fulminant in onset, w/ lower extremity and sacral paresthesias,
difficulty in walking, areflexia, ascending sensory loss and urinary
retention
- rapidly progressive over period of weeks
- w/ predominant neutrophilic pleocytosis
- therapy w/ ganciclovir or foscarnet can lead to rapid improvement
- prompt initiation of foscarnet or ganciclovir therapy is impt in
minimizing degree of permanent neurologic damage
- combination therapy w/ both drugs should be considered in patients
who have been previously treated for CMV disease
Peripheral neuropathies
- common in patients w/ HIV infxn
- occur at all stages of disease and take a variety of forms
- early in course of HIV infxn = acute inflammatory demyelinating
polyneuropathy resembling GBS
- in other patients, progressive or relapsing-remitting inflammatory
neuropathy resembling (CIDP) has been noted
- progressive weakness, areflexia and minimal sensory changes
- CSF examination: mononuclear pleocytosis
- peripheral nerve biopsy: perivascular infiltrate suggesting an
autoimmune etiology
- TX: plasma exchange or IV immunoglobulin = variable success
glucocorticoids = reserved for severe cases of CIDP refractory to
other measures
*Mononeuritis multiplex
- due to necrotizing arteritis of peripheral nerves
*Distal sensory polyneuropathy
- most common peripheral neuropathy in patients w/ HIV
- may be a direct consequence of HIV infxn or a side effect of
dideoxynucleoside therapy
-usually painful burning sensation in the feet and lower extremities
- stocking-type sensory loss to pinprick, temperature and touch
sensation and a loss of ankle reflexes
- motor changes are mild and usually limited to weakness of the
intrinsic foot muscles
- response to antiretrovirals has been variable
- if due to dideoxynucleoside therapy = patients may complain of
sensation that they are walking on ice
- differential dx: DM, Vit B12 def., side effects of metronidazole or
dapsone
- gabapentin, carbamazepine, tricyclics, or analgesics may be effective
for dysthesias
- treatment-naive patients may respong to combination antiretroviral
therapy
- nerve growth factor may benefit some cases
Myopathy
- causes: HIV infxn itself, zidovudine, generalized wasting syndrome
- may range in severity = asymptomatic elevation in creatine kinase
levels to a subacute syndrome characterized by proximal muscle
weakness and myalgias
- variety of both inflammatory and noninflammatory pathologic
processes have been noted in patients w/ more severe myopathy
(myofiber necrosis w/ inflammatory cells, nemaline rod bodies,
cytoplasmic bodies & mitochondrial abnormalities)
- prolonged use of zidovudine = profound muscle wasting often w/
muscle pain
= dose-dependent; reversible following discontinuance
= related to ability to interfere w/ fxn of mitochondrial
polymerases
= red ragged fibers are histologic hallmark
Ophthalmologic Disease
- occur in approximately half of patients w/ advanced HIV infxn
Cotton-wool spots
- most common abnormal findings on funduscopic examination
- hard white spots that appear on the surface of the retina
- often have an irregular edge
- represent areas of retinal ischemia secondary to microvascular
disease
- at times associated w/ small areas of hemorrhage (difficult to
distinguish from CMV retinitis)
- not associated w/ visual loss and tend to remain stable or improve
over time (in contrast to CMV retinitis)
CMV retinitis
- one of the most devastating consequences of HIV infxn
- high risk of CMV retinitis = CD4+ T cell count <100 µL
= should undergo ophthalmologic exam every 3-6 months
- majority occurs in patients w/ a CD4+ T cell count <50/µL
- usually presents as a painless, progressive loss of vision
- patients may also complain of blurred vision, “floaters” and
scintillations
- usually bilateral, affecting one eye more than the other
- diagnosis is made by experienced ophthalmologist
- characteristic retinal appearance = perivascular hemorrhage &
exudates
- vitreous or aqueous humor sampling w/ molecular dx techniques may
be of value
- results in a necrotic inflammatory process
- visual loss is irreversible
- may be complicated by rhegmatogenous retinal detachment as a
consequence of retinal atrophy in areas of prior inflammation
- tx: oral valganciclovir, IV ganciclovir, or IV foscarnet, w/ cidofovir as
an alternative
- combination therapy w/ ganciclovir and foscarnet has been slightly
more effective in patient w/ relapsed CMV retinitis
- 3-wk induction course is followed by maintenance therapy w/ oral
valganciclovir
- if limited to the eye = ganciclovir-releasing intraocular implant,
periodic injections of the antisense nucleic acid preparation
formivirsen, or intravitreal injections of ganciclovir or foscarnet may be
considered
= some combine intraocular implants w/ oral valganciclovir
- maintenance therapy continued until CD4+ T cell count remains >100
to 150/µL for >6 months
- etiology unknown; suggested that this may be due to the generation
of an enhanced immune reactivation syndrome
- in some instances, use of topical glucocorticoids is required
Acute retinal necrosis syndrome or progressive outer retinal
necrosis (PORN)
- associated w/ pain, keratitis and iritis
- often associated w/ orolabial HSV or trigeminal zoster
- widespread pale gray peripheral lesions in ophthalmologic exam
- often complicated by retinal detachment
- impt to recognize & treat w/ IV acyclovir as quickly as possible to
minimize loss of vision
Secondary infection due to P. carinii
- cause a lesion of the choroid that may be detected as an incidental
finding on ophthalmologic exam
- typically bilateral; from half to twice the disc diameter in size
- appear as slightly elevated yellow-white plaques
- usually asymptomatic & may be confused w/ cotton-wool spots
Chorioretinitis due to toxoplasmosis
- seen alone or, more commonly, in association w/ CNS toxoplasmosis
Secondary to Kaposi’s sarcoma
- may involve eyelid or conjunctiva
Secondary to lymphoma
- may involve retina
Additional Disseminated Infections and Wasting Syndrome
Bartonella
- seen w/ increased frequency in patients w/ HIV infxn
- indicative of a severe defect in cell-mediated immunity
- usually seen in patients w/ CD4+ T cell counts <100/µL
- clinical manifestations:
(1) Bacillary angiomatosis – usually due to infxn w/ B.
henselae
- vascular proliferation that leads to a variety of
skin lesions that have been confused w/ the skin lesions of
KS
- lesions generally blanch, are painful and typically
occur in the setting of systemic symptoms (in contrast to KS)
- can extend to the lymph nodes, liver (peliosis
hepatis), spleen, bone, heart, CNS, respiratory tract, and
GIT
(2) Cat-scratch disease – generally begins w/ a papule at the
site of inoculation
- followed several weeks later by development of
regional adenopathy and malaise
(3) infection w/ B. quintana – transmitted by lice
- assoc. w/ case reports of trench fever,
endocarditis, adenopathy, and bacillary angiomatosis
- dx often relies upon identifying organism in
biopsy specimens using Warthin-Starry or similar stains
- tx : either erythromycin or doxycycline for at least
3 months
Histoplasmosis
- generally a late manifestation of HIV infxn
- may be the initial AIDS-defining condition
- median CD4+ T cell count was 33/µL
- disseminated disease due to reactivation is the most common
presentation in HIV-infected patients
- usually present w/ a 4- to 8-week history of fever & weight loss
- hepatosplenomegaly and lymphadenopathy in about 25% of patients
- CNS disease, either meningitis or a mass lesion, in 15% of patients
- bone marrow involvement is common, w/ hrombocytopenia,
neutropenia, and anemia in 33% of patients
- mucocutaneous lesions consisting of maculopapular rash and skin or
oral lesions in approx. 7% of patients
- respiratory symptoms are usually mild, w/ chest x-ray showing diffuse
infiltrate or diffuse small nodules in approx. half of cases
- dx : culturing organisms from blood , bone marrow, or tissue
- tx =amphotericin B, 0.7 to 1.0 mg/kg daily to a total dose of 1g
followed by maintenance therapy w/ itraconazole
=itraconazole alone (mild infection)
Penicillium marneffei
- complication of HIV infection & considered an AIDS-defining condition
in parts of world where it occurs
- 3rd most common AIDS-defining illness in Thailand
- more frequently diagnosed in the rainy than the dry season
- fever, generalized lymphadenopathy, hepatosplenomegaly, anemia,
thrombocytopenia and popular skin lesions w/ central umbilication
- tx: amphotericin B followed by itraconazole
Visceral leishmaniasis
- w/ increasing frequency in patients w/ HIV infxn who live in or travel
to areas endemic for this protozoal infxn transmitted by sandflies
- clinical presentation: one of hepatosplenomegaly, fever and
hematologic abnormalities
- lymphadenopathy & other constitutional symptoms may be present
- dx : cultures of bone marrow aspirates, antibody titers (of little help),
histologic stains (may be negative)
-tx: standard therapy w/ pentavalent antimony compounds
- eradication is difficult; relapses are common
Generalized wasting
- AIDS-defining condition
- involuntary weight loss of >10% assoc. w/ intermittent or constant
fever & chronic diarrhea or fatigue lasting >30 days in the absence of a
defined cause other than HIV infxn
- an indication for initiation of HAART
- severe muscle wasting w/ scattered myofiber degeneration and
occasional evidence of myositis
- tx =glucocorticoids may be of some benefit (must be carefully
weighed against the risk of compounding the immunodeficiency of HIV
infxn)
=androgenic steroids, growth hormone, and total parenteral
nutrition (variable success)
Neoplastic Diseases
Kaposi’s sarcoma
- declined in rates due to use of potent antiretroviral therapy
- multicentric neoplasm consisting of multiple vascular nodules
appearing in the skin, mucous membranes & viscera
- ranges from indolent, w/ only minor skin or lymph node involvement,
to fulminant, w/ extensive cutaneous and visceral involvement
- HHV-8 or KSHV has been strongly implicated as a viral cofactor in
pathogenesis of KS
- has varied presentations
- seen at any stage of HIV infxn, even in presence of normal CD4+ T
cell count
- initial lesion = small, raised reddish-purple nodule on the skin,
discoloration on the oral mucosa, or swollen lymph node
- often appear in sun-exposed areas, particularly the tip of the nose
- have propensity to occur in areas of trauma (Koebner phenomena)
- color ranges from reddish to purple to brown & often take the
appearance of a bruise, w/ yellowish discoloration and tattooing
- size ranges from a few millimeters to several centimeters & may be
either discrete or confluent
- lesions most commonly appear as raised macules; can also be
popular, particularly in patients w/ higher CD4+ T cells
- confluent lesions may give rise to surrounding lymphedema & may
be disfiguring when they involve the face and disabling when they
involve the lower extremities or the surfaces of joints
- lymph nodes, GIT & lung = commonly affected by KS (aside form
skin)
- lesions have been reported in virtually every organ, including heart
and CNS
- lymph node involvement maybe seen very early in KS & is of no
special clinical significance (patients w/ relatively intact immune fxn &
thus w/ best prognosis)
- pulmonary involvement = shortness of breathe
- Pulmonary KS = 80% of patients have cutaneous lesions
= in chest x-ray, bilateral lower lobe infiltrates that obscure
the margins of mediastinum & diaphragm
= pleural effusion in 70% of cases (helpful in differential dx)
- GI involvement = seen in 50% of patients
= takes one of two forms
(1) mucosal involvement – may lead to bleeding that can
be severe
- sometimes also develop symptoms of GI
obstruction if lesions become large
(2) due to biliary tract involvement
- KS lesions may infiltrate the gallbladder and
biliary tree, leading to clinical picture of obstructive jaundice
similar to that seen w/ sclerosing cholangitis
- staging system developed by National Institute of Allergy and
Infectious Diseases AIDS
Clinical Trial Group = distinguishes patients on the basis of tumor
extent, immunologic fxn, & presence or absence of systemic disease
(*see table 173-16 at page 1121)
- dx = biopsy of a suspicious lesion
= histologically, proliferation of spindle cells & endothelial cells,
extravasation of RBCs,
hemosiderin-laden macrophages and in early cases, an
inflammatory cell infiltrate
- differential dx : lymphoma (particularly for oral lesions), bacillary
angiomatosis, & cutaneous mycobacterial infxns
- management = effective antiretroviral therapy will go a long way in
achieving control
= spontaneous regressions have been reported in
the setting of HAART
= if lesion remain quite indolent, can be managed
w/ no specific tx (*see table 173-17 at page 1122)
- fewer than 10% of AIDS patients w/ KS die as a consequence of their
malignancy & death from secondary infxns is considerably more
common
- whenever possible, one should avoid tx regimens that may further
suppress the immune system and increase susceptibility to
opportunistic infxns
- tx = indicated under 2 main circumstances
(1) single lesion or a limited number of lesions are causing
significant discomfort or cosmetic problems, such as w/ prominent
facial lesions, lesions overlying a joint, or lesions in the oropharynx
that interfere w/ swallowing or breathing
tx : localized radiation, intralesional vinblastine, or
cryotherapy may be indicated (doses of radiation directed at mucosal
surfaces, particularly in the head & neck region, should be adjusted
accordingly)
(2) large number if lesions or with visceral involvement
tx : systemic therapy, either IFN-α or chemotherapy
* CD4+ T cell count -single most important determinant of
response (particularly true for IFN-α)
- if >600/µL, response rate is ~80%; if <150µL, response rate
is <10%
= IFN-α - provide an added advantage of having antiretroviral
activity
- may be the appropriate 1st choice for single-agent systemic
therapy for early w/ disseminated disease
= liposomal daunorubicin – approved as first-line therapy for
patients w/ advanced KS
- fewer side effects than conventional chemotherapy
= liposomal doxorubicin & paclitaxel – approved only for KS
patients who have failed standard chemotherapy
- response rates vary from 23-88%; greatly influenced by
CD4+ T cell count
Lymphomas
- occur w/ an increased frequency in patients w/ congenital or acquired
T cell immunodeficiencies (AIDS is no exception)
- develop in at least 6% of all patients w/ AIDS
- not experienced as dramatic a decrease as a consequence of the
widespread use of effective antiretroviral therapy
- occurs in all risk groups, w/ the highest incidence in patients w/
hemophilia and the lowest incidence in patients from the Caribbean or
Africa w/ heterosexually acquired infection
- late manifestation of HIV infxn
- occurring in patients w/ CD4+ T cell counts <200/µL
- as HIV disease progresses, risk of lymphoma increases
- attack rate increases exponentially w/ increasing duration of HIV infxn
& decreasing level of immunologic fxn
- as people w/ HIV infxn live longer as a consequence of improved
antiretroviral therapy & better treatment & prophylaxis of opportunistic
infxns, it is anticipated that the incidence of lymphomas may increase
- approx. 90% are B cell in phenotype & half contain EBV DNA
- may be either monoclonal or oligoclonal in nature
- some way related to the pronounced polyclonal B cell activation seen
in patients w/ AIDS
- 3 main categories:
(a) Immunoblastic lymphomas
- account for ~60% of the cases of lymphoma in patients w/
AIDS
- generally high grade & would have been classified as
diffuse histiocytic lymphomas in earlier classification schemes
- more common in older patients; increasing in incidence
from 0% in HIV-infected individuals <1year old to >3% in those >50
- one variant : body cavity lymphoma
- presents w/ lymphomatous pleural, pericardial, and/or
peritoneal effusions in the absence of discrete nodal or extranodal
masses
- do not express surface markers for B cells or T cells
- HHV-8 DNA sequences have been found in the genome of
malignant cells
(b) Small non-cleaved cell lymphoma
- accounts for ~20% of the cases of lymphoma in patients w/
AIDS
- most frequent in patients 10-19 years old
- usually demonstrates characterictic c-myc translocations
from chromosome 8 to chromosomes 14 or 22
- not commonly seen in the setting of immunodeficiency
other than HIV-associated
immunodeficiency
- over 1000-fold higher in the setting of HIV infxn than in
general population
- only 50% of HIV-associated Burkitt’s lymphoma are EBV-
positive
(c) Primary CNS lymphoma
- accounts for ~20% of the cases of lymphoma in patients w/
AIDS
- usually positive for EBV
- does not have a predilection for any particular age group
- generally presents at a later stage of HIVinfxn than
systemic lymphoma
- poorer prognosis for this subset of patients (median
survival <1 yr)
- presents w/ focal neurological deficits, including cranial
nerve findings, headaches, and/or seizures
- in MRI or CT, limited number (one to three) of 3- to 5-cm
lesions
- lesions often show ring enhancement on contrast
administration & may occur in any location
- locations most commonly involved are deep in white matter
- tx = complicated by the fact that this illness usually occurs
w/ advanced HIV disease
= palliative measures (radiation therapy) provide some
relief
- clinical presentation = quite varied, ranging from focal seizures to
rapidly growing mass lesions in the oral mucosa to persistent
unexplained fever
= at least 80% of patients present w/ extranodal disease
= at least 80% have B-type symptoms of fever, night sweats,
or weight loss
= any site in the body may be involved
= most common extranodal site is the CNS (approx. 1/3 of
patients w/ lymphoma)
-systemic lymphoma = CNS disease in the form of leptomeningeal
involvement
= lumbar puncture is important in staging evaluation
= seen at earlier stages of HIV infxn may commonly involve
the GIT, bone marrow, liver and lung
= GIT involvement – seen in ~25% of patients
- any site may be involved
 - complain of difficulty swallowing or abdominal
pain Antiretroviral Therapy
- usually suspected on the basis of CT or MRI of - combination antiretroviral therapy (HAART) – cornerstone of
abdomen management of patients w/ HIV
= bone marrow involvement – seen in ~20% - suppression of HIV replication is an important component in
of patients prolonging life as well as improving quality of life in patients w/ HIV
- may lead to pancytopenia infxn
= liver & lung involvement – seen in 10% of - currently licensed drugs for treatment of HIV infxn fall into 3
patients categories:
- pulmo disease may present as either mass (a) those that inhibit the viral reverse transcriptase enzyme
lesion, multiple nodules, or an interstitial infiltrate (*see table 173-20 at pages 1125-1127)
= tx - combination chemotherapy (b) those that inhibit viral protease enzyme
- combination antiretroviral therapy (c) those that interfere w/ viral entry
(better results)
* FDA-approved reverse transcriptase inhibitors
Human papilloma virus (HPV) - first class of drugs that were licensed for the tx of HIV infxn
- assoc. w/ intraepithelial dysplasia of the cervix or anus - indicated use as part of combination regimens
- 2x as common in HIV-infected individuals than in general population - block the HIV replication cycle at the point of RNA-
- can lead to intraepithelial neoplasia & eventually invasive cancer dependent DNA synthesis, the reverse transcription step
- only small increases in the incidence of cervical or anal cancer have
been seen as a consequence of HIV infxn Nucleoside Nucleotide Nonnucleoside
- comprehensive gynecologic and rectal exam, including Pap smear analogues analogue reverse transcriptase
indicated at initial evaluation and 6 months later for patients w/ HIV (inhibit a variety of (same as inhibitors
infxn DNA polymerization nucleoside (quite selective for the
* both exams (-) at both time points = patient followed w/ rxns in addition to analogues) HIV-1 reverse
yearly evaluation those of HIV-1 transcriptase)
* initial or repeat Pap smear show severe inflammation w/ reverse transcriptase)
reactive squamous changes = next Pap smear at 3 months zidovudine tenofovir nevirapine
* at any time Pap smear show intraepithelial lesions = didanosine delavirdine
colposcopic exam w/ biopsies should be performed zalcitabine efavirenz
- HAART found to reduce rate of progression and in some instances to stavudine
induce regression of HPV-induced dysplasia lamivudine
abacavir
IDIOPATHIC CD4+ T LYMPHOCYTOPENIA emtricitabine
- characterized by:
(1) an absolute CD4+ T cell count of <300/µL or <20% of
- serious side effects are more common w/ nucleoside analogues
total T cells on more than one occasion
(include mitochondrial damage
(2) no evidence of HIV-1, HIV-2, HTLV-I, or HTLV-II on
that can lead to hepatic steatosis & lactic acidosis as well as
testing
peripheral neuropathy & pancreatitis)
(3) absence of any defined immunodeficiency or therapy
- more recently recognized problems w/ widespread use of HAART
assoc w/ decreased levels of CD4+ T cells
therapy = syndrome of hyperlipidemia, glucose intolerance and fat
- certain patients develop some of opportunistic diseases (particularly
distribution often referred to as lipodystrophy syndrome
cryptococcosis) seen in HIV-infected patients
- demographically, clinically, and immunologically unlike HIV infxn and
Zidovudine
AIDS
- 1st drug approved for tx of HIV infxn
- fewer than half of reported ICL patients had risk factors for HIV infxn
- prototype nucleoside analogue
- wide geographic & age distributions
- act as DNA chain terminators owing to their inability to form a 3’-5’
- many patients remained clinically stable & their condition did not
phosphodiester linkage w/ another nucleoside
deteriorate progressively
- bind much more avidly to the active site of the RNA-dependent DNA
- certain patients experienced spontaneous reversal of CD4+ T
polymerase of HIV
lymphocytopenia
- has a relatively high avidity for the DNA polymerase-γ of human
- ICL patients often have decreases in CD8+ T cells and in B cells
mitochondria & may contribute to the development of fatty liver and
- immunoglobulin levels either normal or, more commonly, decreased
myopathy sometimes observed in patients
- cases widely dispersed, w/ no clustering
taking zidovudine
- a heterogeneous syndrome; highly likely no common cause
- side effects: fatigue, malaise, nausea & headache (at initiation of
- there may be common causes among subgroups of patients that are
therapy)
currently unrecognized
- patients may develop a macrocytic anemia, myopathy,
- patients should be worked up for underlying diseases that could be
cardiomyopathy, & lactic acidosis assoc. w/ fatty infiltration of the liver
responsible for immune deficiency
- resistance = occur ~6 months following the initiation of monotherapy
- if no underlying cause, no specific therapy initiated
= emerges more rapidly in late-stage patients,
- opportunistic diseases should be treated appropriately
presumably as a consequence of greater degree of viral replication
- patients should receive prophylaxis (depending on level of CD4+ T
and thus a greater opportunity for mutation
cell count) for the commonly opportunistic infxns
- Combivir = zidovudine and lamivudine
- Trizivir = zidovudine, lamivudine and abacavir
TREATMENT
General Principles Management
- appropriate use of potent combination antiretroviral therapy and other
tx and prophylactic interventions is of critical importance
- health care provider provide each patient w/ appropriate counseling & Page 1128-1138
education concerning their disease as part of comprehensive care plan
- patients must be educated about the potential transmissibility of their First drug- Tenofovir
infxn Second drug licensed – Didanosine
- important for patients to be aware that the virus is still present and Weakest-Zalcitabine
capable of being transmitted at all stages of HIV infxn 4th drug- Stavudine
- therapeutic decisions should be made in consultation w/ the patient or 5th drug- Lamivudine
the patient’s proxy Hypersensivity- Abacavir
- recommended that anyone about to undergo testing have “pretest
counseling” to prepare him or her at least partially 2. Didanosine- ddl
- health care provider should be prepared to activate support system metabolized to dideoxyadenosine in vivo
immediately for newly diagnosed patient
best absorbed on empty stomach at a HIGH pH thus
- several examinations & laboratory studies that should be performed
contains a buffer
to help determine the extent of disease & provide baseline standards
for future reference (*see table 173-18 at p1124) each dose administered in 2 tablets to ensure adequate
- CD4+ T cell count, 2 separate plasma HIV RNA levels, a VDRL test, buffering of stomach acid or as an extended-release enteric-
and an anti-Toxoplasmosis antibody titer be obtained (in addition to coated capsule
routine chemistry & hematology MOST COMMON TOXICITY: painful; sensory peripheral
screening panels & chest x-ray) neuropathy if >400 mg/d; resolves with discontinuation and
- PPD test should be done doesn’t recur if given in a reduced form
- patients be immunized w/ pnuemococcal polysaccharide and
hepatitis A & hepatitis B vaccines (if seronegative for these viruses) discontinue if abdominal pain consistent with fatal
- status of hepatitis C infxn should be determined pancreatitis
- patients counseled w/ regard to sexual practices & needle sharing
 discontinue if increased serum amylase or lipase with an - among the best-tolerated PI.
ultrasound of edematous pancreas
B. Ritonavir
CONTRAINDICATION: history of pancreatitis - at full doses, ritonavir is poorly tolerated
- main side effects: nausea, diarrhea, abd.pain,
3. Zalcitabine- ddC circumoral paresthesia
 Rarely used, weakest nucleoside analogues - high affinity with isoforms of cytochrome P450
 MOST COMMON TOXICITY: pancreatitis - increase glucoronyltransferases activity
- pharmacodynamic boosting property with 100-200mg
4. Stavudine- d4T 2x daily
 Thymidine analogue zidovudine and Stavudine are - when given with low dose ritonavir, saqunavir and
antagonistic drugs and never be given together! indinavir can both be given 2x daily and taken with
 MOST COMMON TOXICITY: peripheral neuropathy and food.
hepatic steatosis
 Commonly used with lamivudine as initial treatment C. Indinavir
- first PI used in dual nucleoside therapy
5. Lamivudine- 3TC - first triple combination: Zido + Lami + indinavir
 Used in combination regimen with Zidovuidne (Combivir) or - Indinavir: nephrolithiasis and asymptomatic indirect
either alone hyperbilirubinemia/ metabolized by liver/ lowered if with
 Excellent synergy with other nucleoside analogue because cirrhosis
HIV strains resistant (M184V substitution) to lamivudine - To avoid potential for cardiac arrhythmias or prolonged
appear to have enhanced sensitivity sedation, terfenadine, astemizole, cisapride, triazolam,
midazolam should NOT be given to patients taking
 Among the best tolerated and least toxic nucleoside
indinavir because they share metabolic pathways.
analogues
D. Nelfinavir and amprenavir
6. Emtricitabine FTC
- Nelfinavir resistance is associated with a D30N
- negative enantiomer of a thio analogue of cytidine with a
substitution in the protease gene.
fluorine in the 5 position
- Amprenavir resistance is associated with a unique
- combination drug
substitution at amino acid 50
- Associated with M184V mutation in reverse transcriptase
- GI side effects for both
like lamivudine
- Amprenavir causes severe skin reactions
- K65R mutation have reduced susceptibility with FTC
- Disadvantage of Amprenavir: 8 large capsules 2x a day.
7. Abacavir
E. Fosamprenavir (Lexiva) prodrug of amprenavir and
- Synthetic carbocyclic analogue of the nucleoside guanosine
converted to amprenavir by cellular phosphatases/ combined
- combination drug
with ritonavir.
- Hypersensitivity reactions like fever, skin rash, fatigue and GI
symptoms and be discontinued and not to restart it.
F. Lopinavir/Ritonavir (Kaletra)
- Fatal hypersensitivity with rechallenge!
- fixed dose combination of protease inhibitors lopinavir
- HLA-B57 are susceptible to hypersensitivity
and ritonavir.
8. Tenofovir disoproxil fumarate
- Advantage: it combines the pharmacologic
- acyclic nucleoside phosphonate diester analogue of
enhabncement of low-dose ritonavir with a second PI in
adenosine monophosphate.
a single capsule.
- Undergoes diester hydrolysis to form tenofovir
- Combination drug
G. Atazanavir (Reytaz)
- Increased resistance if K65R mutation HIV strains
- azapeptide inhibitor
- Eliminated by kidneys
- associated with increases in serum bilirubin and
- Don’t give if with renal impairments
prolongations of the PR interval
- Coadministration with didanosine leads to increase in
- 150L substitution is responsible for resistant strains
didanosine levels.
- inhibitor of cytochrome P3A and its use may be
associated with increased levels of Calcium Channel
9. Nevirapine, delavirdine and efavirenz
Blockers, HMG-CoA reductase inhibitors and
- nonnucleoside inhibitors
sildenafil
- Combination drugs
- MOA: Inhibits reverse transciptase by binding to regions of
FUSION INHIBITOR ENFUVIRTIDE (Fuzeon)
enzyme outside the active site and causing conformational
-The newest class of retroviral compounds are the entry
changes in the enzyme that render it inactive
inhibitors that act by interfering with the binding of HIV to its receptor or
- Very selective for HIV-1
co-receptor or by interfering with the process of fusion.
- No activity against HIV-2when used monotherapy, rapid
- enfuvirtide is a linear amino acid synthetic peptide
emergence of resistance
- composed of amino acid residues and interferes with the
- Efavirenz once a day
fusion of the viral and cellular membranes by binding to the
- Nevirapine given 2x a day
HR1 regions of the gp41 subunit of the HIV-1 envelope.
- Delavirdine given 3x a day
- Eradication of HIV infection has not been possible.
- END: Maculopapular rash within first weeks, rule out
- HIV infection is a chronic infection.
Stevens-Johnson syndrome by looking carefully for signs of
- Reasonable initial treatment: antiviral therapy in:
mucosal involvement, significant fever pr painful lesions with
i. acute HIV syndrome
desquamation
ii. symptomatic patients
- Nevirapine: Fatal hepatotoxicity, fulminant and cholestatic
iii. asymptomatic disease CD$ ,250/ uL or >50,000 copies
hepatitis, hepatic necrosis and hepatic failure
of HIV RNA per mL
- Efavirenz: light-headedness, dizziness, vivid dreams. Thus
- 6 wk course therapy for uninfected but high-risk of
taking at bedtime minimizes side effects.
exposures
- The initial regimen is usually the most effective insofar as the
Initial regimens: HIV-1 Protease inhibitors plus reverse transcriptase
virus has yet to develop significant resistance.
inhibitors has been shown to suppress HIV replication to under 50
- Initial therapy: 2 different 3-drug regimens
copies per milliliter.
- First regimen: 2 nucleoside analogues (lamivudine) plus a
HIV protease inhibitors appear to be good substrates for the drug
non-nucleoside reverse transcriptase inhibitors
transporters MDR-1 and MRP-2.
- Second regimen: 2 nucleoside analogues and a protease
inhibitor
HIV-1 Protease Inhibitors:
- Following the initiation therapy: expect tenfold (1 log0
-drugs metabolized by Cytochrome P450: Saquinavir, indinavir,
reduction in plasma HIV RNA level within 1 –2 months and a
macrolide antibiotics, R-warfarin, ordansetron, rifampin, CCB,
rise in CD4 T cell count of 100-150/uL.
glucocorticoids, chemotherapeutic drugs.
- Change in therapy if this endpoint is not achieved. And if
CD4 T cell count is persistent, clinical deterioration or drug
A. Saquinavir
toxicity.
- first licensed
- When changing therapy because of treatment failure (clinical
- hard gel (Invirase) with poor bioavailability
progression or worsening laboratory parameters), it is
- soft-gel (Fortavase) good plasma levels. Esp. if
important to attempt to provide a regimen with at least two
combined with ritonavir
new drugs.
- metabolized by: cytochrome P450 system and Ritonavir
- In the patient in whom a change is made for reasons of drug
inhibits this system thus increase in saquinavir
toxicity, a simple replacement of one drug is reasonable.
plamsma levels if combined
- Drug toxicity will begin showing reversal of signs 1-2 weeks.
 - The simpler the therapeutic regimen, the easier it is for the • Practice of safer sex
patient to be compliant. Plasma HIV RNA levels and CD4 be o Most effective way of prevention for sexually active
monitored every 3-4 months. uninfected individuals & for infected individuals to
- The inhibitory quotient, defined as the trough blood avoid spread of infection
level/IC50 of the patient’s virus is used by some to determine • Abstinence from sexual relations
the adequacy of dosing of the given treatment regimen. o Only absolute way to prevent sexual transmission
- Immune based therapies are being developed as more is of HIV
discovered about the role of the immune system in
• Use of condoms
controlling viral replication.
o Not 100% effective in preventing transmission of
Table 173-23 Indications for the initiation of Antiretroviral Therapy in HIV
Patients with HIV infection o Breakage or improper use
1. Acute infection syndrome • Most common cause of condom failures
2. Chronic infection • Latex condoms – preferable
a. Symptomatic disease • Receptive fellatio
b. Asymptomatic disease o Definitely not safe sex
b.1 CD4+ T cell <350/ul • Kissing
b.2 HIV RNA >50,000 copies mL or increasing o Considered safe
3. post exposure prophylaxis
 Due to low conc. of virus in saliva of
infected Pt & (+) in saliva of HIV
Please read:
inhibitory proteins
1. Table 173-21 Drug-to drug interactions involving
• Prevention among IDUs
Antiretroviral agents
2. Table 173-22 principles of therapy of HIV infection o Stop use of injectable drugs
3. Table 173-24 Indications for changing Antiretroviral therapy o Avoidance of sharing of needles & other
in patients with HIV infection paraphernalia
4. Figure 173-41 candidate HIV Vaccines o Paraphernalia should be cleaned after each usage
5. Figure 173-40 “Amino Acids substitutions conferring w/a virucidal solution
resistance to antiretroviral drugs • Transmission via blood transfusion
o Decreased by
HIV AND THE HEALTH CARE WORKER  Screening blood donors for both HIV Ab
• Have a small but definite risk of becoming infected with HIV & p24 Ag
as a result of professional activities.  Heating of clotting factor concentrates
o 0.3% - following percutaneous exposure to HIV  Autologous transfusion
contaminated blood
o 0.09% - after mucous membrane exposure • Treatment of HIV infected mother w/ antiretroviral during
• Needle sticks injuries pregnancy & infant during 1st wks following birth
o Causes most cases of worker seroconversion o Decreases mother to child transmission of HIV
o 27% - improper disposal • HIV can be transmitted via breast milk & colostrums
o 23% - during attempts to start IV line o Breastfeeding from an infected mother should be
o 22% - during blood drawing avoided if at all possible
o 16% - IM or SQ injection
o 12% - giving IV infusion
Alex G
• Factors that increase risk of occupational transmission of David
HIV Gayl
o Deep injury Bernice
o (+) blood on the instrument causing the exposure EJ
o Injury w/a device that had been placed in the vein Sheryl
or artery of source Pt Marilou
o Terminal illness in the source Pt
o Lack of postexposure antiretroviral therapy in
exposed health care worker “What I don’t know won’t hurt me.”
o Pregnancy in the health care worker “ Not knowing is the worst feeling in the world.” – Grey’s Anatomy
o Exposure to drug resistant virus “We have to be in-the-know.”
• Postexposure prophylaxis
o For routine exposure
• 2 nucleoside analogue reverse
transcriptase inhibitors for 4wks
o For high risks or complicated exposure
• 2 nucleoside analogue reverse
transcriptase inhibitors + 3rd drug for
4wks
• Minimizing risk of occupational HIV infection
o Adherence to universal precautions
o Refraining from direct Pt care if 1 has exudative
lesions or weeping dermatitis
o Disinfecting & sterilizing reusable devices
employed in invasive procedures
• Infections common to HIV infected Pt that can be transmitted
to health care worker
o HBV
o TB

VACCINES
• Problems in development of safe & effective vaccine for HIV
o High mutability of virus
o Infection can be transmitted by cell free or cell
associated virus
o Need for development of effective mucosal
immunity
o Difficult to establish the precise correlates of
protective immunity to HIV infection

PREVENTION
• Cornerstones of HIV prevention
o Education
o Counseling
o Behavior modification