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x. ID > 4/28 HIV Lecture, Ch 15, Ch 16 > Flashcards

4/28 HIV Lecture, Ch 15, Ch 16 Flashcards

1
Q

A few historical facts:

When were the first published reports of HIV?

Earliest cases?

First diagnostic test available?

AZT available?

Protease inhibitors licensed?

AIDS mortality declines in US?

A

When were the first published reports of HIV: 1981

Earliest cases: Probably 1930-50 in Africa, 1950s in US

First diagnostic test available: 1985 (antibody)

AZT available: 1986

Protease inhibitors licensed: 1995

AIDS mortality declines in US: 1997

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2
Q

Estimate of # people living with HIV infection in US?

Globally?

(what is the world’s population?)

A

US: 1 million

Global: 42 million

World pop’n: 7.2 billion (7200 million)

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3
Q

what are the 3 modes of transmission?

A
  • Sexual
  • Parenteral (blood transfusion, IVDU, needle stick)
  • Perinatal
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4
Q

There are 2 types of global transmission patterns.

Where do they predominate?

M:F ratios?

Transmission mech? Types of people are infected?

A

Type I: North America & Europe.

M:F ratio 10:1, homosexual men, IVDUs, rare perinatal cases.

Population seroprevalance <1%

Type II: Sub-Saharan Africa, Haiti.

M:F ratio 1:1, Heterosexual transmission, blood, unsterilized needles, significant perinatal spread

Population seroprevalence > 1%

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5
Q

Local HIV epidemiology: # patients at Dartmouth HIV program?

infected in NH, VT?

A

Dartmouth HIV treats ~500

NH: 1000

VT: 700

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6
Q

Projections for prevalance in sub-saharan africa? Eastern Eur? India? SE Asia?

A

sub-saharan africa: thought to be saturated

Eastern Eur, India, SE Asia: predicted to have rapid rise

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7
Q

What are the relative risks of the parental modes of transmission (screened blood, IVDU, needle stick)?

A

screened blood: < 1/500,000

IVDU: 6/1000

HIV pos needle stick: 3/1000 without prophylaxis

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8
Q

what is the % transmission from mom to child (perinatal)? how can we reduce that risk?

A

in US: 25%.

With AZT prophylaxis, 8%

With HIV Rx for mother/infant, 1%

in Africa: 35%

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9
Q

What other viruses is HIV closely related to?

A

Transforming retroviruses: Mammalian, Avian, HTLV-I, HTLV-II

Cytopathic retroviruses (aka lentiviruses): Visna, HIV-2, SIV (simian immunodef virus), HIV-1 (the one we think of as HIV)

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10
Q

Structure of the virus?

A

Note:

lipid bilayer

Single-stranded HIV RNA

Protease

Integrase

Reverse transcriptase

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11
Q

What is a clade? What are the different subtypes of HIV-1?

A

Clade = subtype.

HIV-1 Group M (“Major”) is divided into clades:

Africa: subtypes A, B, C

US: subtype B

Thailand: subtypes B and E

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12
Q

What are the important parts of the HIV life cycle for which inhibitors have been developed?

A

More on this in the HIV Pharm lecture

  1. Viral penetration and uncoating
  2. Reverse transcription
  3. Transcription
  4. Assembly
  5. Release -> progeny
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13
Q

What are the 4 main stages of HIV infection?

A
  1. Infection
  2. Seroconversion
  3. Clinical latency (asymptomatic)
  4. AIDS (symptomatic)
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14
Q

Describe the Infection stage of HIV

A

M-(macrophage)-trophic phenotype infects macrophage or dendritic cell (on mucosal surface if sexually transmitted).

Uses both CD4 and CCR5 receptors (aka C5 phenotype).

\Infection spreads to regional lymph nodes.

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15
Q

Describe the Seroconversion stage of HIV

A

Burst of viremia accompanied by mono-like seroconversion syndrome in up to 50% of patients, 4-8 weeks after infection. Cytotoxic CD8 cells, and also antibody to viral envelope, reduce viral replication to lower “setpoint” which varies in different individuals.

(Viral load is typically 50% lower in women)

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16
Q

Describe the Clinical Latency stage of HIV

A

Asymptomatic.

Most patients remain free of clinical sx for 10-12 years. Viral load remains stable; CD4 falls slowly at a rate of 50-75 cells/year.

This apparent “steady state” is actually a dynamic process with large scale viral replication leading to progressive emergence of numerous resistant quasi-species (“swarm of HIV”)

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17
Q

Describe the AIDS/symptomatic stage of HIV

A

Viral phenotype evolves to T-trophic (T-lymphocyte-trophic) phenotype using both CD4 and CXR4 receptors (aka X4 phenotype). Produces marked increase in proportion of infected circulating CD4 lymphocytes and rapid fall in CD4 count to < 200 (defines AIDS).

T trophic (or syncytium inducing =SI) strains also cause clumping of CD4 lymphocytes.

Clinical immunodeficiency becomes apparent with susceptibility to numerous opportunistic infections. Death results 2-3 yrs from opp infections, tumors, and progressive wasting.

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18
Q

What features of human hosts can influence susceptibility to infection?

Specifically, what genetic change reduces infection risk?

what genetic change will delay disease progression?

A

Genetic polymorphisms in chemokine co-receptor genes:

Infection risk reduced in pts with homozygous deletion in CCR5 (the second receptor for the M-tropic HIV). These pts are essentially immune to HIV

Disease will progress more slowly in pts homozygous for deletion in CCR5 (as above) and for pts with CXCR4 mutations (the second receptor for T-trophic HIV)

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19
Q

Prevention for sexual transmission?

Parenteral transmission?

Perinatal transmission?

A

Sexual: condoms, education, post-exposure prophylaxis

Parenteral: blood screening, methadone programs, bleach for needles, needle exchange

Perinatal: screening/counseling, C-sections, HIV Rx during preg or at time of delivery

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20
Q

(from student-asked questions in class)

Pt = HIV+, 35yo woman. Lives in trailer in rural West virginia. Presents with blurry vision, floaters, light flashes/changes. On Opthalmic exam, see retinal detachment, white infiltrates, hemorrhage.

What treatments should you use?

(what does she have?)

A

She has CMV retinitis (opportunistic when CD4 count is < 50)

  • IV ganciclovir or oral valganciclovir if mild lesion
  • Opthalmic implant if vision is threatened
  • Due to low CD4 count, may want to treat prophylactically against other opportunistic infections
  • Treat HIV with antiretrovirals
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21
Q

(from student-asked questions in class)

24 year old male, CD4 count = 90. Has AIDS. Does not take his antiretroviral drugs. For past week has had a headache (worst symptom), also has been sweaty and fatigued.

Best method of diagnosis?

(options: Blood culture, MRI, PAS stain, CSF antigen)

Also, what is treatment? Prophylaxis?

A

Pt has cryptococcal meningitis

Diagnose via CSF antigen

(CSF is under super high pressure, may squirt into the test tube w puncture!)

Tx = ampho B & 5 flucytosine. May put in shunt to unload pressure.

Prophylaxis = fluconazole.

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22
Q

(from student-asked questions in class)

HIV+ patient, CD4 count = 47. Has been swimming in hot spring (in the upper valley). Productive cough with sputum, fever, night sweats, weight loss.

Lung exam: crackles

Culture reveals acid-fast bacteria.

Treatment? Prophylaxis?

A

Patient has Mycobacterium Avium.

(if patient had been from elsewhere it could have been TB)

Treatment: Clarithromycin + rifabutin + ethambutol (don’t need to know treatment per Lahey)

Prophy: Weekly azithromycin or rifabutin

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23
Q

List the following in approximate descending order of risk of HIV infection:

  • IVDU
  • fellatio
  • cunnilingus
  • receptive anal
  • receptive vaginal
  • insertive anal
  • insertive vaginal
A
  • IVDU & receptive anal - tie for first!!
  • insertive anal (note everything anal is higher risk than anything vaginal)
  • receptive vaginal
  • insertive vaginal
  • fellatio
  • cunnilingus
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24
Q

CDC recommendation for screening of US adults?

A

recommendation is that all US adults be screened at least once in lifetime for HIV infection regardless of risk factors in an “opt out” fashion.

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25
Q

what is the risk of transmission from mother to child during vaginal birth?

during breastfeeding?

A

1 in 4 for each

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26
Q

Beyond specific behaviors, what variables modify the likelihood of HIV transmission?

A

-when infected partner has high viral load (during primary HIV infection)

(though transmission occurs even when load is undetectable)

  • mucosal ulceration
  • needle stick: severity of injury, degree of soiling, type of needle
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27
Q

what cell is the primary target of HIV infection?

what subset of these cells does it infect in particular?

A

Primary target = CD4+ helper cell

particularly activated and HIV-specific CD4+ cells (smart little bugger)

some CD4+ cells are converted into virus factories, others serve as hideouts for the virus

28
Q

Within a few weeks of new infection, what are cytokines doing?

CD8+ cytolytic T cells?

what is happening to the CD4+ T cells?

A

Vigorous and HIV-specific immune response: cytokines “flying left and right”

CD8+ cytolytic T cells express granzyme and perforin

CD4+ T cells are dying in huge numbers (60-90% die during the first few weeks of infection)

29
Q

What happens to the HIV viral load in response to the initial immune response?

why can the immune system not completely the HIV virus?

A

In response to initial immune response, HIV load declines a lot.

-Unable to completely clear the virus, likely due to HIV’s ability to mutate, virus’s ability to become latent in resting cells (hides from immune system)

30
Q

What is actually killing the CD4+ T cells that are infected with HIV?

A

the immunological activation that follows HIV infection is thought to be what kills so many cells and leads to immunodeficiency

31
Q

What does the physical presentation of acute HIV infection look like?

A

Mono-like illness: fever, headaches, fatigue, rash, 2-4 weeks post-infection

Non-specific findings.

(CNS findings also found in acute HIV; mono is more associated with pharyngitis)

32
Q

For acute HIV infection, will HIV serology be positive or neg?

HIV viral load?

A

For suspected acute infection, check both

HIV serology: negative until the host has created antibodies

HIV viral load: astronomically high. Therefore this is the cornerstone of acute HIV diagnosis

33
Q

What is “viral escape”?

A

after acute HIV infection, chronic HIV sets in…. virus replicates and evolves due to pressure from immune system. If host immune system targets a particular peptide, the virus mutates until it is unrecognizable.

34
Q

Why is the immune system at a disadvantage in the battle against HIV?

A

HIV-specific CD4+ T cells are targeted by the virus.

Losing battle… partly due to strain on bone marrow’s ability to generate new cells

35
Q

which is thought to be a bigger problem of HIV infection: infection and deletion of immune cells, or chronic immune activation?

A

chronic immune activation thought to be larger contributor to “deranged immune responses” seen during HIV infection

36
Q

HIV causes what problems in non-immune cells – ie other body systems?

A
  • harms neurons in the brain and periphery
  • chronic inflammatory state thought to inc risk for CV disease
  • progressive risk of cancer due to insertion into genome
  • psychiatric disease = important problem (partly due to chronic disease, partly because mental illness may contribute to HIV acquisition and complicate its course)
37
Q

what are the symptoms of chronic HIV infection?

A

essentially asymptomatic

(a minority of pts: fatigue, diffuse lymphadenopathy, end-organ dysfunction)

38
Q

What is the viral set point? what does it help determine?

A

clinical milestone early on in chronic HIV infection: establishment of “set point”. Steady state HIV viral load detected in plasma 1 yr after infection.

Helps predict prognosis (high set point -> progress faster to AIDS)

39
Q

What test is used to diagnose chronic HIV?

A

HIV serology - done by ELISA.

99.9% sensitive. If positive, confirm with Western Blot

40
Q

What is the CD4 count used for clinically?

A

Figuring out where a patient is in the spectrum of disease.

Do they still have a working immune system? or are they at risk for opportunistic infections?

CD4 count shapes need for prophylactic antibiotics and need for antiretriviral therapy.

41
Q

What is the CD4 count under which it is reasonable to start treatment?

A

CD4 count of 500 = threshold below which it is reasonable to start treatment.

Also, the presence of opportunistic infections and other symptoms from HIV infection can also prompt treatment

42
Q

worldwide, what is the leading cause of death in people with HIV?

what is the relative risk for pneumonia in pts with HIV?

A

Leading cause of death in pts with HIV is tuberculosis

people with HIV have 150x rate of pneumococcal pneumonia & 100x rate of pneumonia from H influenza.

43
Q

why are people with HIV at risk for co-infections with chronic viruses?

A

Hep B and Hep C share risk factors with HIV

they are also worsened by HIV infection

HIV infected patients are less likely to clear either virus

HIV patients have more rapid and frequent hepatic decompensation from Hepatitis

44
Q

in most developed world HIV clinics, what is the leading cause of death?

A

liver disease (presumably from Hep B and Hep C)

45
Q

HIV infection results in a predisposition for cancers that arise from what?

what is a classic example?

A
  • HIV impairs immunologically-mediated surveillance for cancer
  • predisposed to cancers arising from **chronic viral infection **

-Lymphoma is classic example – due to infection by EBV.

-Also HPV-related cancers (cervical, anal) are higher in HIV patients

46
Q

CD4 count below 200: what infection should we think of?

What is the classic presentation?

Treatment?

Prophylaxis?

A

Below 200: PCP

Presents as bilateral pneumonia with hypoxia

Treatment: trimethoprim/sulfamethoxazole (TMP/SMX)

Prophylaxis is same ^

47
Q

CD4 count below 100: what infection should we think of?

What is the classic presentation?

Treatment?

Prophylaxis?

A

Below 100: toxoplasmosis

Ring-enhancing lesion on imaging

Treatment: pyrimethamine-sulfadiazine

Prophy: TMP/SMX

48
Q

CD4 count below 50: what infection should we think of?

What is the classic presentation?

Treatment?

Prophylaxis?

A

Below 50: MAC

Febrile wasting syndrome

(diagnosed via blood culture)

Tx: combination therapy (2-3 drugs for 12 months – only cure is a functioning immune system)

Prophy: weekly azithromycin

49
Q

CD4 count <50 - 100: what infection should we think of?

What is the classic presentation?

Dx?

Treatment?

Prophylaxis?

A

Cryptococcal meningitis

Non-specific presentation w fever, pneumonia, meningitis

Dx: lumbar puncture for CSF; look for cryptococci

Tx: amphotericin B + flytocytosine

Prophy: Fluconazole

50
Q

Toxoplasma encephalitis: what is the parasite?

what will be revealed on scanning?

hard to distinguish from what?

A

Toxoplasma gondii

mass lesion in CNS -> ring-enhancing lesion

can look like primary CNS lymphoma (dx via trial of medication or brain biopsy!)

51
Q

cryptococcal meningitis: what is the parasite?

A

cryptococcus neoformans

52
Q

what do we do for all patients with CD4 counts below 50?

A

prophylaxis against MAC with weekly azithromycin

53
Q

CD4 count below 50 and optical issues - what is the possible disease?

what patients are at risk?

Presentation?

Treatment?

Prophylaxis?

A

CD4 below 50 + vision issues -> Cytomegalovirus retinitis

  • only CMV+ patients are at risk!
  • in HIV, CMV can cause a vision-threatening retinitis
  • blurry vision, light flashes, floaters, scotomata

Tx: IV ganciclovir or oral valganciclovir, or opthalmic implants

54
Q

Patients with CD4+ below 50 and who are CMV positive: what do we check on a regular basis?

A

regular opthalmic exams – vision problems in AIDS pts are an emergency!

(w all these patients, Siedlecki can buy his second Hummer!)

55
Q

What is the difference between HIV 1 and HIV 2? how were each transmitted to humans?

A

HIV-1 is far more common.

Both HIV 1 and HIV 2 were transmitted from chimps to humans (bush hunters) – each was transmitted separately but via the same mechanism

HIV 2 is a less severe phenotype BUT it is resistant to a class of drugs - uncommon to have HIV 2 but good to know for treatment.

56
Q

What is R0? (“R-naught”)

What is the R0 for HIV?

How does that compare with R0 for other diseases?

A

R0 describes the spread of an infection in a population.

R0 < 1: infection will not be sustained through a population; will eventually die out. (Ex: Ebola: people don’t live long enough to transmit it)

R0 must be > 1 for disease to self-perpetuate. A higher R0 indicates a more rapid spread of disease

HIV: R0 = 2-5. Not hugely transmissible

For comparison: Measles = 12-18, Smallpox= 5-7, Influenza = 2-3

57
Q

What is the reason for the CDC recommendation that all people get tested for HIV at least once, regardless of risk factors?

A

25% of HIV-pos people don’t know they have it.

58
Q

The fact that HIV preferentially kills activated CD4+ cells (the ones that are activated to respond), memory CD4+ cells, and HIV-specific CD4+ cells has what effect?

What effect does losing other memory CD4+ cells have on general immune reponse?

A
  • The cells that are most prepared to fight HIV are the ones that die first - HIV specific responses disappear very quickly in patients who have HIV infection
  • lose other memory cells as well –> prone to other infections
59
Q

Until recently we thought that HIV caused Productive Infection of a minority of cells, causing apoptosis in those cells. What is our new understanding of how HIV causes immunodeficiency?

What is abortive infection v productive infection?

A

New understanding: HIV causes Abortive infection of most cells, and Productive infection in a small minority of cells.

Abortive Infection: HIV enters cells, but the virus does not complete its entire life cycle. HIV fragments are enough to cause immune activation. This causes a form of apoptosis called Pyroptosis (mediated through Caspase 1). Now thought to be the major component of HIV infection.

Productive Infection: Causes apoptosis mediated through Caspase 3. Now thought to be a minor component of HIV infection.

60
Q

What is the main cause of AIDS: Pyroptosis or Apoptosis? which caspase mediates this process?

A

Pyroptosis, mediated through Caspase 1.

61
Q

Two reasons why 33% of transmission occurs during the transmitter’s acute HIV infection?

A
  1. Highest viral load at this point -> most infectious.
  2. Person unlikely to be aware they are HIV+, thus not taking precautions to protect others
62
Q

Using the train metaphor, what test tells you how close you are to the cliff (ie, how much damage has been done)?

What test tells you how fast the train is moving (ie, how fast the damage is occuring)?

A

how much damage has been done: CD4 count

how fast the damage is occuring: viral load

63
Q

What is a normal CD4 count?

Under 200, what opp inf occurs?

under 100?

under 50 (name 4)?

A

normal CD4 count: 800

Under 200: PCP

under 100: Toxoplasmosis

under 50: MAC, CMV retinitis, cryptococus, Kaposi sarcoma

64
Q

CD4 count below 50, purplish lesions: what disease?

Presentation?

Due to what virus?

Treatment?

A

Kaposi’s Sarcoma

Presentation = purplish bumps, possibly lymphadenopathy, fever, cough

Sarcoma due to infection from HHV-8

Treatment = HAART

65
Q

What other infections are HIV+ people likely to have or acquire (beyond those that we think of at certain CD4 counts)?

A

Co-infection with Hep B, Hep C, Herpes Zoster, Candida (thrush)

66
Q

What psychiatric issues may be present in HIV+ patients?

A

Psychiatric disease is very prevalent: more than 60% of HIV+ pts have a psych dx.

  • partly due to strain of having a chronic disease
  • some had it prior to HIV; psych issues may have driven HIV acquisition due to low self care etc
67
Q

Three populations (in the US) that we characterize as particularly high-risk?

A

IVD users: 22x risk

Commerical Sex workers: 13.5x risk

Gay men: 1 in 5 (whoa)

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