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Flashcards in M36: HIV and AIDS Deck (27)
1

The Epidemiology of HIV

1. _ was discovered as the etiologic agent of AIDS in 1984; 3 years after the first cases were reported. Two years later, _ was isolated in AIDS patients from West Africa.

2. Although both types have the same modes of transmission and associated opportunistic infections, _ is a milder form and progresses slower than _. Infection with HIV-2 is endemic to (country), where the virus must have been in circulation since the 1960s or 70s.

3. At the end of 2012, there is an estimated 35.3M people infected with HIV worldwide. About 71% of the total number of infected persons live in (country) where nearly 1 in every 20 adults is living with HIV. Close to 26 million people are eligible for _ under the WHO 2013 consolidated guidelines.

4. The number of people dying of AIDS-related causes in 2012 was 1.6M. There were 2.3M new infections in 2012, 260,000 of which were in _.

1. HIV-1
HIV-2

2. HIV-2
HIV-1
West Africa

3. Sub Saharan Africa
antiretroviral therapy (ART)

4. children (

2

The Epidemiology of HIV

5. More than 1.1M people in the US are infected with HIV; a prevalence of 0.5%. Almost 1 in 6 (15.8%) are _ of their infection, probably contributing to the approximately 50,000 new infections yearly. Of the 15 US cities with the highest rates of new HIV diagnoses, 11 are in the _ US (including (6)).

6. In the US, _ comprise around 50% of people living with HIV and 63% of all new infections. _ accounted for 27% of all infections and approximately 25% of new infections. _ represent 16% of all infections.

7. _ constitute 14% of the US population and are disproportionately affected with an estimated 44% of new HIV infections. _ women account for nearly 2/3 (64%) of new infections among women.

8. The epidemiology of chronic HIV is changing in the era of effective _ as there is an increasing burden of non-AIDS illness such as (3).

5. unaware
Southeastern
Miami, New Orleans, Jackson, Memphis, Atlanta, and Houston

6. men who have sex with men (MSM)
Unprotected heterosexual sex
IV drug users

7. African-Americans
African-American

8. ART
cardiovascular disease, metabolic diseases, and non-AIDS-associated malignancies

3

HIV Transmission:
Common Modes

a. _: homosexual, bisexual, heterosexual (most common worldwide)

b. _ with shared needles

c. _: occurs in utero and intrapartum. Without intervention, the transmission rate is ~25%. If _ is given during pregnancy, the transmission rate can be reduced to

a. Sexual intercourse

b. Injection drug use

c. Vertical transmission (mother to child)
antiretroviral therapy (ART)
Caesarian section

d. Breastfeeding postpartum

4

HIV Transmission:
Uncommon Modes

a. _ of contaminated _ or _ (1 in 2.135M)

b. _ of infected organs

c. _ of health workers with _ contaminated by infected persons: transmission rate is 0.3%.

A study showed that post-exposure prophylaxis with _ can reduce needle stick transmission by 80%. The risk is further decreased if 2 or 3 _ drugs are used (this is the current recommendation).

Health care workers should (always / never) recap needles and should (always / never) practice Universal Blood and Body Fluid precautions.

a. Transfusion
blood or blood products

b. Transplantation

c. Accidental inoculations
needles

zidovudine (AZT/ZDV)
antiretroviral

never
always

5

Review of the Viral Structure and Life Cycle
HIV Structure

a. The virus consists of (#) identical strand(s) of (DNA / RNA) with associated enzymes that are enclosed in a cone-shaped _ _ protein.

b. The envelope consists of a lipid bilayer membrane containing viral _.

c. The envelope viral glycoprotein is a _ complex consisting of a transmembrane _ and an external _ subunit.

a. two
RNA
p24 capsid

b. glycoproteins

c. trimeric
gp41
gp120

6

Review of the Viral Structure and Life Cycle
HIV Life Cycle (Fig 1)

a. The viral glycoprotein binds to _ which is expressed on the surface (3).

b. When CD4 binds to _, it causes a conformational change in the glycoprotein allowing it to further bind to the chemokine coreceptors, _ or _ (depending on virus coreceptor tropism), which then exposes the fusion domain of gp41 allowing the fusion of _ and _ membranes and subsequent _.

c. The viral genome is released in the _ and the associated enzymes are activated.

d. The _ enzyme transcribes the HIV _ to a (ss/ds)(DNA/RNA) which is then integrated into the host DNA by the _ enzyme

e. Transcription of the viral DNA then occurs followed by the production of _.

f. The _ enzyme cleaves the newly synthesized viral polypeptide into _ components which are assembled in the _ to make new viral particles that are then released from the cell.

a. CD4
T helper cells, macrophages, and dendritic cells (DCs)

b. gp120
CCR5 or CXCR4
viral and host
viral entry

c. cytoplasm

d. reverse transcriptase
RNA
double stranded DNA
integrase

e. viral proteins

f. protease
functional viral protein
cytoplasm

7

Natural History and Prognosis of HIV-1 Infection Without Treatment

1. A primary or acute HIV-1 infection syndrome may last _.

2. A long period of “_” follows primary infection during which there may be _. This period lasts for 8-10 years on average, but is variable. Around 20% of patients progress to _ within five years of infection, but ~ 12% remain _ for more than 20 years.

3. The duration of clinical latency is related to the level of _. The higher the level, the (longer / shorter) the latent interval and time to AIDS and death. What determines the level of viremia is not clearly defined but includes human and viral _.

4. Symptoms generally occur when the _ count declines to

1. 2-6 weeks

2. clinical latency
no symptoms
AIDS
AIDS-free

3. viremia
shorter
genetics

4. CD4+ T-cell
200
higher
viremia and/or opportunistic

5. AIDS
CD4+T-cell
200
opportunistic

6. children
children

8

HIV Pathogenesis

1. HIV-1 infects mainly _ (in blood and tissues) and _ (in brain and spinal cord).

2. CD4+T-cells are killed by _ of infected cells and by activation of _ which can trigger apoptosis.

3. Virus production is (large / small) and (fast / slow) (1010 virions/day), as is CD4+T-cell destruction.

4. The host response is _ (antibodies and cell-mediated immunity) but _ effective in suppressing virus production.

5. High _ and the error prone _, which copies the single-stranded RNA viral genome into double-stranded DNA, generate billions of genetically distinct _. In fact, the rapid evolution of the virus is thought to begin at the peak of anti-HIV-specific _ cell response early in infection.

1. CD4+ helper T-cells
macrophages/microglia

2. single cell lysis
uninfected cells

3. large
fast

4. vigorous
only partially

5. viral turnover
reverse transcriptase (RT)
viral variants
CD8+ T

9

HIV Pathogenesis

6. These variants escape the host’s _ responses (antibodies and CD4+ and CD8+ T-cells) as well as _ therapies and cause _ destruction and disease progression.

7. Chronic HIV infection is associated with _ immune activation and increased levels of systemic _ which increases target cell availability and promotes _ and increased _.

8. T-cell _ fails to keep pace with _, leading to progressive CD4+T-cell depletion, immunodeficiency, and death as a consequence of _ infections and malignancies.

9. Organ dysfunction in HIV infection and AIDS can result from:

a. Direct effects of _ (eg: AIDS dementia complex)

b. _ reaction to the virus (eg: thrombocytopenia)

c. Secondary infection by _ pathogens which may either be _ (eg: cytomegalovirus) or invasion by organisms that _ most people but are not pathogenic in normal hosts (eg: Pneumocystis)

d. Increased systemic _ and persistent immune activation

6. immune
antiretroviral
CD4+T-cell

7. persistent
inflammation
viral replication
apoptosis

8. regeneration
destruction
opportunistic

a. HIV

b. Immune

c. opportunistic
reactivation of latent infections
colonize

d. inflammation

10

Diagnosis of HIV-1 Infection

1. Screening test: newer generation _

2. Newer generation tests can be reactive in as early as 3 weeks from the time of infection.

3. Confirmatory test: _ or _ (alternative test)

4. Specimens that are positive in the screening test but negative or indeterminate in the confirmatory test should be tested with an _ test for _. Detectable HIV RNA indicates the presence of _ infection. Viral RNA can be detected in as early as 7-10 days from the time of infection.

5. For neonatal infection, maternal antibodies produce false (positive / negative) ELISA tests. Serum _ antigen or PCR for HIV-1 DNA or RNA are useful for diagnosis.

1. ELISA

3. HIV-1/HIV-2 antibody differentiation (Multispot) assay or Western Blot

4. FDA-approved nucleic acid
HIV-1 RNA
acute HIV-1

5. positive
p24

11

Clinical Manifestations of HIV-1 Infection and AIDS
Acute Infection

a. An acute illness associated with HIV-1 _ has been reported in 53-93% of patients.

b. This usually occurs around 2-4 weeks from transmission and is referred to as _. This disease mimics infectious _.

c. Symptoms can include: (10).

d. Laboratory findings include (3).

e. Diagnosis is made by clinical suspicion and a positive PCR for _ since the antibodies may not be present at this time.

a. seroconversion

b. Acute Retroviral Syndrome
mononucleosis

c. fever, lethargy, malaise, myalgia, headaches, sore throat, rash, oral ulcers, neck stiffness, and lymphadenopathy

d. lymphopenia (with atypical lymphocytes), neutropenia, and hepatitis

e. HIV-1 RNA

12

Clinical Manifestations of HIV-1 Infection and AIDS
Chronic HIV-1 Infection and AIDS

a. Oral Manifestations: _ (Thrush)

– treat with topical (_) or systemic antifungal therapy (e.g. _)

b. Cutaneous Manifestations: Viral

HSV-1 or HSV-2
– vesicles that evolve into painful _ with raised margins; _ and _ locations most common
– treat with oral _ (IV if severe)

_ (Shingles)
– usually one _, may be _/_ (2 or more dermatomes), recurrent, or chronically persistent
– treat with high-dose oral _ (IV if disseminated) and analgesics

Oral Candidiasis

- clotrimazole
fluconazole

- ulcers
oral and perianal
- (val)acyclovir

Varicella Zoster Virus
- dermatome
multidermatomal/disseminated
- (val)acyclovir

13

Clinical Manifestations of HIV-1 Infection and AIDS
Chronic HIV-1 Infection and AIDS

Gastrointestinal Manifestations: Hepatobiliary Disease

_ Complex (_)

– usually infiltrates the _ and _

– in AIDS, almost always _ and not _ disease

– may present with _, decreased _, elevated _ enzymes

– best diagnosed with _

– treat with a combination of 2-3 drugs; active drugs include: (4)

Mycobacterium avium (MAC)

- portal triads and liver parenchyma

- disseminated
pulmonary


- hepatomegaly
blood counts
liver

- blood cultures

- azithromycin, rifabutin, ethambutol, and amikacin

14

Clinical Manifestations of HIV-1 Infection and AIDS
Chronic HIV-1 Infection and AIDS

Pulmonary Infections: Pneumocystis jiroveci Pneumonia (PJP or PCP)

– insidious onset of (3)
– chest x-ray shows _
– diagnosed by detecting organisms with _ or _ stain of induced sputum or bronchoalveolar lavage specimen

Therapy (4)

Prevention
– start _ for CD4+T-cell counts

- fever, dyspnea, nonproductive cough
- bilateral interstitial infiltrates
- silver methenamine or toluidine blue

– trimethoprim/sulfamethoxazole (TMP/SMZ)
– pentamidine IV
– atovaquone
– corticosteroids improves survival in severe disease

- TMP/SMX

15

Clinical Manifestations of HIV-1 Infection and AIDS
Chronic HIV-1 Infection and AIDS

Pulmonary Infections: Mycobacterium tuberculosis (Mtb)

– incidence of Mtb in patients with AIDS is almost 50 times the incidence in the general population
– initial evaluation of all HIV(+) patients should include _ testing with _ or _
– the risk of _ latent Mtb among HIV(+) patients is estimated to be 8%/year
– a 5mm reaction (induration) to PPD is considered (positive / negative) for HIV(+) persons; these patients should receive treatment for latent TB infection for 9 months

Therapy:
– initial meds include: (4)
– emergence of _ Mtb is a major problem in certain regions of the country (eg NYC), particularly in (4) and factors and prevent medication adherence
– if drug resistance is considered a possibility, patients should be treated initially with a _ regimen until susceptibility results are available about 6 weeks later
– therapy should be given promptly and compliance monitored
– _, which is resistance to all first-line anti-TB medications is a growing problem in Southern Africa and is associated with a high mortality (>50%)

- skin
PPD or TB-interferon gamma release assay (IGRA)
- reactivating
- positive

- Rifampin/Rifabutin, Isoniazid, Pyrazinamide, Ethambutol
- drug-resistant
alcoholics, drug users, homeless persons, and those incarcerated due to crowding
- 5-6-drug
- extreme drug resistant TB (XDR-TB)

16

Clinical Manifestations of HIV-1 Infection and AIDS
Chronic HIV-1 Infection and AIDS

Central Nervous System and Ocular Infections: Toxoplasmosis

– most common cause of _ in AIDS patients
– patients are Toxoplasma _(+)
– reactivation from latent _

Symptoms
– change in _
– _
– focal _ signs (50%)
– generally _ onset (days to weeks)

Diagnosis – usually multiple _ by CT scan with contrast

Treatment – _ / _ or _ / _

- CNS mass lesions
- IgG
- cysts

- mental status
- headaches
- neurologic
- subacute

ring-enhancing lesions

sulfadiazine / pyrimethamine or clindamycin / pyrimethamine

17

Clinical Manifestations of HIV-1 Infection and AIDS
Chronic HIV-1 Infection and AIDS

HIV-Related Malignancies

i) _ - is the most common malignancy reported in persons with AIDS. Manifests as focal, vascular _ in skin or other organs. Caused by _ or _. Treat with ART, systemic interferon, radiation, or chemotherapy.

ii) _ - becoming more uncommon as _ are more effectively treated and prevented. Usually occurs in patients with CD4 counts

i) Kaposi’s Sarcoma (KS)
nodules
human herpesvirus 8 (HHV-8) or KSHV (Kaposi Sarcoma Herpes Virus)

ii) Non-Hodgkin’s Lymphoma
OIs
B-cell
central nervous system

18

Antiretroviral Therapy of HIV-1:
Nucleoside analog reverse transcriptase inhibitors (NRTIs)

a. Mechanism of action
i) Phosphorylation to _ by cellular enzymes
ii) Bogus substrate for _
iii) Once incorporated, it terminates the _ chain

b. Examples (5)
Combinations: (3)

c. Some known adverse effects (4)

i) 5’-triphosphate
ii) RT
iii) DNA

i) Zidovudine; AZT or ZDV
ii) Lamivudine; 3TC
iii) Emtricitabine; FTC
iv) Abacavir; ABC
v) Tenofovir; TDF
Combivir (AZT/3TC) Truvada (FTC/TDF) Epzicom (3TC/ABC)

i) Bone marrow suppression (AZT)
ii) Renal insufficiency (TDF)
iii) Pancreatitis (DDI)
iv) Hypersensitivity reaction (ABC)

19

Antiretroviral Therapy of HIV-1:
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

a. Mechanism of action
i) _ inhibitor
ii) Binds to a _ and “freezes” the enzyme so it _

b. Examples (2)

c. Some known adverse effects (3)

i) Non-competitive (Do not inhibit substrate binding)
ii) hydrophobic pocket
cannot catalyze polymerization

i) Efavirenz; EFV
ii) Nevirapine; NVP

i) CNS: dizziness, vivid dreams (EFV)
ii) Rash (EFV and NVP)
iii) Hepatitis (NVP)

20

Antiretroviral Therapy of HIV-1:
Protease Inhibitors (PIs)

a. Mechanism of action
i) _ is essential for the maturation of virions into infectious particles.
ii) _ cleaves the large _ and _ polyproteins into structural proteins and enzymes
iii) _ compete with the normal substrate for binding _ hence blocking its activity

b. Examples (3)

c. Some known adverse effects (3)

i) HIV-1 protease
ii) Protease
gag and gag-pol
iii) PIs
protease

i) Ritonavir; (now only used as a pharmacologic booster of other PIs)
ii) Atazanavir; ATV
iii) Darunavir; DRV

i) Diarrhea (NFV, LPV/r)
ii) Mild hyperbilirubinemia (ATV, IDV)
iii) Kidney stones (IDV)

21

Antiretroviral Therapy of HIV-1:
Fusion Inhibitors (Enfuvirtide; T-20)

a. 35 amino acid peptide that binds to the _ protein of the _ envelope and blocks the normal coil-coil interaction required for the fusion of the _ and _

b. Administered by _ twice daily

c. Not suitable for _ therapy when other treatment options are available

d. May cause _ in the site of injection

a. gp41
HIV-1
viral and host membranes

b. subcutaneous injection

c. initial

d. subcutaneous nodules

22

Antiretroviral Therapy of HIV-1:

Integrase inhibitors/ Integrase Strand Transfer Inhibitors (INSTI)

a. Mechanism of action: _ is essential for proviral DNA integration into host chromosomal DNA

b. Examples (1)

c. Well-tolerated?

Entry inhibitors (Maraviroc; MVC)

a. Occupies the _ co-receptor and blocks virus entry

b. Not active against virus that can use the alternate _ co-receptor

c. Requires a diagnostic test to determine _ usage of the patient’s virus

a. HIV integrase

b. i) Raltegravir; RAL (requires twice daily dosing)

c. Yes

a. CCR5 HIV-1

b. CXCR4 HIV-1

c. co-receptor

23

Antiretroviral Therapy of HIV-1:

Combination ARTs (1)

Benefits of ART
a. Increases _ cell counts
b. Delays progression to _
c. Helps decrease risk for consequences of chronic immune activation such as (3)
d. Prolongs _
e. Decreases _

Atripla: Efavirenz – Tenofovir – Emtricitabine

a. CD4+ T
b. AIDS
c. cardiovascular diseases, metabolic diseases, and malignancies
d. survival
e. transmissibility

24

Antiretroviral Therapy of HIV-1:

a. Requires _ treatment; drug compliance necessary

b. ART is recommended for _

c. In the USA, initiation of ART is strongly recommended for the following individuals
i) Anyone with symptomatic _ or _ or with a history of an _-defining illness
ii) Patients with CD4+ T cell count

a. lifelong

b. all HIV-infected individuals

i) HIV or AIDS
AIDS
ii) 500
iii) nephropathy
iv) Hepatitis B
anti-Hep B
v) Pregnant

i) NRTI
FTC/TDF (Truvada)
ii) an NNRTI, a ritonavir-boosted PI, or an INSTI
iii) Three

25

Prevention of HIV Infection

Important obstacles

a. Years of _ during which transmission to others (can / cannot) occur
b. Inability to tell _ from _ (other than by serological tests)
c. Human _ and the desire to _
d. Vaccine?
e. _ stigma and fear of _

The outcome of preventive measures greatly depends on:

a. _ compensation
b. Uptake of _
c. Access to _

As such, HIV prevention should involve _ as there is _ that will have 100% uptake of intervention and 100% access to target population.

a. silent infection (asymptomatic
can
b. who is infected from who isn’t
c. libido
procreate
d. No effective vaccine available in the near future
e. Social
testing

a. Risk
b. intervention
c. target population

multiple strategies as there is no one strategy

26

Approaches to HIV prevention

a. _ of everyone (especially the youth) about the risk of HIV-1 infection and other sexually transmitted infections

b. _: sexual abstinence, mutually faithful monogamy

c. _ protection (male or female _)

d. Regular HIV testing for _ populations

e. Treatment as _ (up to 96% reduction in serodiscordant heterosexual couples)

f. _ (50% reduction)

g. _: oral antiretrovirals and topical microbicides

h. _

i. _ which includes screening of ALL pregnant women and initiation of ART during pregnancy

j. Substitute for _

a. Education

b. Behavioral modification

c. Barrier
condoms

d. high risk

e. prevention

f. Circumcision

g. Pre-exposure prophylaxis

h. Post-exposure prophylaxis

i. Prevention of maternal to child transmission (PMTCT)

j. breastfeeding

27

Is HIV Eradication Possible?

1. A 40 year old, HIV-1 infected patient, virally suppressed on antiretroviral therapy, presented with leukemia and underwent _ with peripheral blood stem cells from a donor who was homozygous for the _ delta32 allele. His plasma _ remained below the limit of detection even after antiretroviral therapy was discontinued.

2. A follow-up paper reported that the patient remains without any sign of HIV infection. HIV remained undetectable in different _ compartments.

3. A neonate born to an HIV-1(+) woman was started on _ within 30 hours of birth. After _ was discontinued at 18 months of age, plasma HIV-1 RNA continued to be undetectable through 30 months of age.

4. The report of this first ever HIV-1 cure as well as the report of the “_” has reinvigorated research into developing strategies for HIV eradication.

5. Barriers to HIV eradication include:
a. Presence of long-lived _ infected cells
b. Presence of _ viral replication (at least in some patients)
c. Presence of _ that have limited penetration of ART

6. Current research studies are evaluating different strategies to counter these barriers to HIV eradication

1. stem cell transplantation
CCR5
HIV-1 RNA

2. tissue

3. ART
ART

4. Mississippi baby

a. latently
b. residual
c. anatomical reservoirs