00:01
So, what are those opportunistic
infections?
And those are called, variably,
opportunistic infections,
AIDS-defining infections, or in this case,
AIDS indicator diseases,
and they are many.
00:13
And they correlate with how
immunosuppressed the patient is from
the attack on the CD4 count.
00:19
We'll start with bacterial infection,
and these can be
bacterial infections which normally
have limited
virulence, limited pathogenicity.
00:29
For example, a nontuberculous
or an atypical
mycobacterium avium-intracellulare
complex.
00:37
This is known frequently as MAI or
MAC -- Mycobacterium Avium Complex.
00:43
Normally, this causes only rare disease
occasionally in children causing
chronic lymph nodes.
00:49
But in patients with HIV, it can cause
disseminated disease causing
lung disease, pneumonia, enteric disease
with exaggerated
enteric lymph nodes.
00:59
And it is typically seen when the patient
is very immunosuppressed.
01:02
Their CD4 count, not percentage,
but number of CD4 cells per
milliliter of 00:01:11.020
Similarly, these patients can develop
normal mycobacterium.
01:13
Tuberculosis, extra pulmonary
tuberculosis.
01:16
They develop pneumococcal sepsis,
salmonella sepsis,
name the bacteria, and they can develop
overwhelming disease from any of those.
01:25
Viral infections especially are known
to be cytomegalovirus
and chronic or disseminated herpes
simplex virus.
01:33
So, too, as immune discovery wanes,
they can be at risk for escalation
or activation of JC
virus causing progressive multi-focal
leukoencephalopathy.
01:44
Fungal infections, anything and
everything.
01:47
So, candidiasis, a very simple yeast.
01:50
Candida which exists everywhere causes
thrush in children who are nursing
from perhaps
a slightly infected breast.
01:59
The candidiasis can be overwhelming,
and it goes
not just from the mouth, it's
not just thrush
in a patient with HIV, but it travels
all the way
down through the GI collecting system.
02:09
Not just the esophagus,
but including even
intestine to where it can
limit absorption.
02:15
There can be pulmonary candidiasis.
02:17
There can be anything and everything.
02:20
Cryptococcal meningitis, that's
a classic one.
02:23
Cryptococcus is an environmental
mold, which
in most immunocompetent people
doesn't do anything because we
have enough
enough immune discovery to limit that,
and it's typically addressed
by macrophages.
02:37
But in an HIV patient with a CD4
count 00:02:45.460
the ability to stimulate macrophages by
interferon -- alpha and interferon gamma
is limited, as we just talked about.
02:48
Thus these patients are at risk for
cryptococcal meningitis.
02:51
Similarly, histoplasmosis, another
fungal mold,
pneumocystis jiroveci,
which used to be known as pneumocystis
carinii, PCP. It's now PJP.
03:01
It causes a diffuse
interstitial pneumonia.
03:04
All these are seen in patients who are
starting to lose their CD4 count.
03:09
Protozoal infections such as
cryptosporidiosis,
cerebral toxoplasmosis as the patient
gets to a CD4 count.
03:17
And then they can develop cancers because
the proliferating cells don't have
any control
due to an absence of natural
killer cell function,
CD8 cellular or cytotoxic function.
03:30
And then, unrelated necessarily to the
opportunistic infections,
but still certainly quite common is HIV
wasting syndrome.
03:39
And there is a massive weight of research,
pardon the pun,
which has been aimed at trying
to identify
why patients with progressive
HIV infection
lose so much weight.
03:50
And it's not just fat, but it's fat,
muscle, you name it.
03:54
So, how do we diagnose HIV infection?
Well, there are many
screening tests including fourth
generation screening tests,
basically all looking for evidence of
specific antigens to HIV.
04:07
Diagnostic tests for HIV typically start
with an enzyme linked immunosorbent
assay or ELISA.
04:14
Originally,
one had the third generation ELISA
which tested for IgM and IgG antibody.
04:20
This test would become positive.
04:21
20 to 30 days after exposure.
04:24
However, the preferred and currently
recommended test is a fourth generation
ELISA test,
sometimes also known as the combo test.
04:32
This test
as well as the third generation test
for IgM and IgG antibody,
but also the P24 antigen.
04:40
And it can become positive
from 15 to 20 days after exposure.
04:45
If the ELISA is positive,
a confirmation testing by a rapid
HIV one slashes to every two antibody
differentiation assay
is necessary to distinguish
HIV one from HIV two infection.
04:57
HIV two infection is more often
endemic in West Africa.
05:01
Western blot is rarely used anymore
for confirmation,
primarily because it takes too long
and is less sensitive.
05:08
The reverse transcriptase PCR or RT-PCR testing
is sort of the gold standard
at this point, and it is indicated
if you're serologic testing via ELISA or
possibly western blot is in determinant.
05:23
Also, PCR testing is indicated,
if there is suspected acute infection,
but the patient is possibly in the window
period of HIV seroconversion
meaning the time
before a fourth generation
ELISA might turn positive.
05:37
So within the first
really two to three weeks.
05:40
PCR testing
also indicated for diagnosis
of neonatal HIV infection.
05:45
This makes sense.
05:46
If you remember that mom's HIV positive
mothers will transfer IgG of all types
across the placenta.
05:55
So doing an ELISA
test on a baby will only detect
or likely only detect maternal HIV IgG,
which is not helpful.
06:04
Instead, we need a specific test
for the baby to demonstrate
the presence of RNA. PCR testing
also then indicated to screen blood donors
because it's rapid and very sensitive
and a viral load or a quantitative
RT-PCR can be used for the management
and follow up
of HIV one positive patients
as well as for diagnosis.
06:26
The viral load, as it's known,
is really quite sensitive
and in fact there are two quite
sensitive assays.
06:34
One has a sensitivity cut off of 50 copies
per milliliter.
06:37
That's 50. 5 0 copies per milliliter
and detects
virus from ten to 15 days after exposure.
06:44
The ultra sensitive cutoff is from one
to five copies per milliliter of blood.
06:51
And this detects virus, you know,
even as early as five days after exposure.
06:55
That that's incredibly sensitive.
06:58
We'll look at the number
and the percentage of
CD4-positive T lymphocytes in the
peripheral blood.
07:04
Here's an important factor for
use clinically
Patients may have a low CD4 number
if their total number of circulating
white blood cells
is low as well.
07:15
It kind of makes sense.
07:16
So it's far more sensitive look
at the percentage
of the lymphocytes which are CD4-positive
or the percentage which are not
When the percentage drops below 15%,
15%, that is when one is in trouble and
can expect to have a specific
targeting action on the CD4-positive
T lymphocytes.
07:36
Another way which is also
quite sensitive
is to look at the ratio between CD4-positive
and CD8-
positive T lymphocytes.
07:44
Normally, in healthy individuals,
that ratio is 2 -- 2:1.
07:50
In somebody with active HIV
infection or active
retroviral attack on the CD4 cell,
that ratio typically drops to 0.5 --
1:2.
08:00
It's a significant difference and
it's quite sensitive.
08:04
HIV treatment, ideally
and per recommendation treatment
should begin as soon as diagnosis is made.
08:10
Some same day of diagnosis treatment
should start that day
and continue
indefinitely without interruption.
08:17
No more does one recommend
the HIV treatment holidays or honeymoons
as people used to. Drug resistance testing
via HIV genome, whether it's it's
phenotypic
or genotypic, is ordered at the same time,
but the therapy is not delayed
while waiting for those results.
08:36
One also tests for hepatitis B and C
due to the likely cold
tracking of these infections with HIV
and women of childbearing age
also have a pregnancy test.
08:47
The treatment, as stated, is started
regardless
of viral load
or CD4 count or anything else,
and one of three regimens
is usually recommended initially.
08:57
Each of these regimens
includes three HIV medicines
from at least two different
HIV drug classes.
09:05
An example of a typical initial regimen
and a nonpregnant adult
who is treatment
naive is Dolutegravir, which is an integrase
inhibitor and tenofovir, a nucleotide
analog reverse transcriptase inhibitor
plus either emtricitabine
or lamivudine nucleoside reverse
transcriptase inhibitors.
09:27
That's just one example.
09:28
Of course, there are many others.
09:30
Treatment is modified then,
depending on the patient's characteristics
such as pregnancy, age, results of drug
resistance testing, viral load testing,
especially if the patient does not have
or does not demonstrate viral suppression
after initiation of their treatment.
09:47
And of course, side effects.
09:49
The Food and Drug Administration
in the United States has approved
medications in nine different classes
to treat HIV infection.
09:56
And these medications exist
in 23 distinct drug combinations
incorporating at least two HIV medication
types in one pill.
10:05
The classes are nucleoside reverse
transcriptase inhibitors or NRTIs, non
nucleoside reverse
transcriptase inhibitors or NNRTIs
protease inhibitors, PIs, fusion
inhibitors, CCR five antagonists,
integrase strand transfer
inhibitors or INSTIs attachment
inhibitors.
10:29
Post attachment
inhibitors and pharmacokinetic enhancers.
10:33
Turning to human t lymph
a trove of virus type one or HTLV Type one.
10:38
This is a retrovirus and is known
to be associated with two diseases,
even though less than 5% of infected
individuals develop the disease.
10:47
The two diseases are adult T-cell
leukemia, lymphoma or ATLL
and HTLV one associated myelopathy/tropical spastic
paraparesis
or HAM/TSP.
11:03
Clusters of high end immensity of HTLV
one infection have been found
in southern Japan, the Caribbean, areas
of South America and Tropical Africa,
as well as specific foci in the Middle
East, Australia and Melanesia.
11:18
There are an estimated ten to 20 million
HTLV one carriers worldwide,
with about nine cases
per 100,000 people in the USA.
11:28
Interestingly,
it seems to preferentially impact
or infect women
more than men at a ratio of two to one.
11:35
Nearly all HTLV one
infected individuals remain asymptomatic
throughout the infection.
11:41
The incidence of adult T-cell
leukemia lymphoma
ATLL in the USA is about
0.5 cases per 100,000.
11:50
The long term risk of developing ATLL
after infection with HTLV one
is about two to 5%
with onset after 20 to 30 years or more.
12:00
HTLV one associated myelopathy/tropical spastic paraparesis
or HAM/TSP
has a long term risk after infection
of about 2%
with an average onset at 3.3 years.
12:13
Although there's a wide range
from four to 30 years.
12:17
Note the HTLV two
has only rarely been associated with HAM/TSP
and has no definite
causal association
with ATLL or other diseases.
12:30
Looking at transmission HTLV one typically can occur via
breastfeeding
a non barrier sexual intercourse
so no condoms
sharing of needles, blood transfusions,
especially in resource poor countries
and very rarely
in intra-uterine transmission.
12:46
The pathogenesis of HTLV
one infection occurs
after an initial infection of CD4 T
lymphocytes as the primary target.
12:55
However, unlike HIV,
that infection does not cause death
initially of the CD4 T lymphocytes.
13:02
Rather, it causes cell proliferation,
genetic instability
and then malignant transformation
into CD4 lymphocyte clones.
13:11
The exact mechanism
of how this occurs is still unknown.
13:14
Apparently the neoplastic transformation
is mediated through viral gene products,
which interact and interfere
with the host proteins.
13:23
There are two major viral proteins
identified
Tax and HBX. Tax seem to be
the one that we know most about,
Clinically, ATLLl or adult t cell leukemia
lymphoma
is diagnosed by demonstrating malignant
but mature CD4 positive t lymphocytes
with an abnormal convoluted nuclei
which appears flower like an on stain
and seeing the
these abnormal cells in the peripheral
blood lymph nodes and even skin.
13:52
Clinically, these patients unfortunately
have a very low five year survival rate
and they are poorly responsive
to chemotherapy, although bone marrow
transplant may be successful.
14:02
They may show skin lesions,
lytic bone lesions,
hepatosplenomegaly
and immunosuppression.
14:09
Hypercalcemia is a common presentation
because a pair of neoplastic syndrome
related to the release of cytokines,
including parathyroid hormone
related protein PTH-RP, tumor necrosis
factor beta and interleukin
one and RANKL
or receptor activated of nuclear
factor kappa Beta ligand.
14:30
HTLV Lymphotropic Virus type one pathogenesis
in the setting of the associated
myelopathy/tropical spastic paraparesis.
14:39
So have HAM/TSP.
14:40
In this case, HTLV one induces
a proinflammatory response
through the infected CD4 positive
or CCR for positive cells
especially if there are high pro
viral loads of HTLV one.
14:54
This then induces or provokes
a strong virus specific immune response
which is associated with detectable
high anti Tax antibody levels.
15:04
Elevated levels of pro-inflammatory
cytokines and chemokines,
and then a chronic vascular lymphocytic
and macrophage infiltrate.
15:13
If this occurs or when this occurs
in spinal cord and brain,
it causes inflammation
leading to tissue damage
and then axonal myelin and loss,
especially in spinal cord.
15:23
In this, that leads
to the clinical presentation of H.AM/TSP.
15:28
The clinical aspect of HAM/TSP
initially starts with laboratory
findings of HTLV one antibodies
or even antigens demonstrated in the blood
and cerebrospinal fluid. In the CSF
one may also see mild
increases in lymphocytes as well as mild
increases in protein. One
then can find lobulated lymphocytes
with the flower like nuclei described
previously in blood and or spinal fluid.
15:55
Clinically, patients with HAM/TSP
or demonstrated
slowly progressive weakness and spasticity
of one or both legs along with hyperreflexia and ankle
clonus
extensor planter responses in lumbar pain.
16:10
They may demonstrate Detusor
instability presenting as nucturia,
urinary frequency and incontinence.
16:16
They may have sensory changes such
as paresthesias and loss of vibration sense.
16:21
And of course, they'll
have other neurologic manifestations
across the whole spectrum.
16:25
Interestingly, however, cognition
and upper limbs are usually not affected.
16:31
MRI of the brain and spinal cord
may be normal,
or it may demonstrate high intensity
signal on T2 weighted sequences,
which would suggest inflammation
and swelling.
16:41
White matter lesions
in the subcortical and periventricular
regions
may actually mimic multiple sclerosis.
16:47
So considering a differential diagnosis
of multiple sclerosis,
one should also think of HTLV one infection and HAM/TSP.
16:56
The prognosis,
unfortunately, is a steadely progressive
onset from normal function
to wheelchair bound
and total loss of neurologic function
by a median of 21 years.
17:11
And there is no effective treatment