Cohn: Clinical Aspects of AIDS

Question 1

Mother to child transmission without treatment:

Answer 1

24%

Question 2

Routes and frequencies of transimssion (without treatment or intervention)

Receptive anal intercourse:
Insertive anal intercourse:
Receptive vaginal intercourse:
Insertive vaginal intercourse:
Effect of condoms:

Answer 2

Receptive anal intercourse 1-2%;
Insertive anal intercourse 0.06%;
Receptive vaginal intercourse 0.1-0.2%,
Insertive vaginal intercourse 0.03-0.14%.

Condoms reduce risk 1-2 logs.

Question 3

Factors affecting sexual HIV transmission:

Answer 3

i. Genital and plasma HIV RNA levels in source patient
ii. Ulcerative and inflammatory STDs in either partner
iii. Lack of male circumcision increases risk of male acquisition
iv. Mucosal trauma during sex
v. Women have greater biologic susceptibility, and often social susceptibility, than men

Question 4

Effect of plasma HIV RNA (viral load) on transmission:

Answer 4

i. Among HIV infected women giving birth, the risk of transmission to the infant is strongly correlated with the plasma HIV RNA level of the mother near delivery.
1. Other factors besides maternal viral load also influence transmission
ii. Among discordant couples and in absence of antiretroviral therapy, transmission was measured to be very low, near zero, in persons with very low plasma HIV RNA levels (under 400), with higher transmission rates at higher CD4 counts.
iii. Randomized placebo controlled trial of antiretroviral treatment of the infected partner in discordant heterosexual partners reduced transmission within the partnership by 96%.

Question 5

How many virions cause the initial HIV infection?

Answer 5

Initial HIV infection is caused by one or a few founder virions.

Question 6

Reverse transcriptase

How often are single point mutations?
How large is the HIV genome?

Answer 6

As an RNA polymerase it is error prone, introducing a single point mutation about every 10,000 base pairs

As the HIV genome is just under 10,000 base pairs, approximately one mutation is introduced every time a new host cell is infected.

Question 7

Reverse transcriptase

What can occur over the course of a day?
What happens in an infected individual?

Answer 7

In a day of uncontrolled HIV replication producing a billion of new virions, each mutation can occur tens of thousands of times.

Although an individual acquiring HIV infection actually acquires only one or a few founder virions, within a short time those individuals are infected with a swarm of genetically variant HIV. The swarm includes virions with every possible non-lethal, single point mutation and probably some multiple mutations.

Question 8

HIV life cycle in cell populations and tissues

What happens to activated CD4+ cells?
How many virions are produced daily?
How many lymphocytes destroyed and replaced daily?

Answer 8

Activated CD4+ lymphocytes rapidly replicate virus and die in the process

1 - 10 billion virions produced daily in steady state

Up to 1 billion CD4+ lymphocytes destroyed and replaced daily.

Question 9

Evolving paradigm of HIV pathogenesis

Relationship between viral load and rate of CD4 decline:
Effect of immune activity:
Immune activation may be caused by:

Answer 9

Correlation exists between viral load and rate of CD4 decline, but many other factors are also important

Immune activation causes dysregulated immunity and can lead to premature aging (senescence) of the immune system.

Immune activation may be caused directly by the virus, or by bacterial antigens (LPS) leaking from the intestine during early HIV infection

Question 10

Evolving paradigm of HIV pathogenesis

Monocytes:

Answer 10

Host cells slowly replicating virus and surviving

Question 11

Evolving paradigm of HIV pathogenesis

Latently infected cells:
What do these cells harbor?
How can they act?

Answer 11

Resting CD4+ memory cells containing non-replicating HIV DNA.

These cells, obtained from treated patients whose virus can no longer be detected in plasma, harbor replication competent pro-viral DNA and act as a library of all the viral mutations which occurred during the host person’s infection.

Question 12

Where does most HIV replication occur?

Answer 12

Most HIV replication occurs in lymphoid tissue

Question 13

What tissues may harbor virus replicating independently? (2)

Answer 13

Central nervous system

Reproductive tract

Question 14

What will a cure require the end of?
Eradication of?

When is there intense viral replication in the lymphoid tissue in intestinal mucosa?

Answer 14

A cure will require the end of viral replication, plus the eradication of virus from latently infected cells and perhaps from protected sites in various tissue compartments.

During early HIV infection, there is intense viral replication in the lymphoid tissue in the intestinal mucosa

Question 15

Most HIV replication occurs in the lymphoid tissue

What is viral replication in the lympoid tissue in the intestinal mucosa associated with?

The effect in measures of peripheral blood lymphocytes:

Answer 15

Viral replication in the lympoid tissue in the intestinal mucosa is associated with a dramatic decrease in the number of CD4 T-lymphocytes in the gut, including memory cells and cells with mixed chemokine receptors.

This destruction is not obvious in measures of peripheral blood lymphocytes.

Question 16

Immunologic consequences of destruction of CD4+ lymphocytes by HIV

What does the destruction of large numbers of CD4 lymphocytes lead to?

What does CMI defend against?

Answer 16

Loss of cell mediated immunity through the destruction of large numbers of CD4 lymphocytes, which coordinate the cell-mediated immune response.

Cell mediated immunity defends against intracellular pathogens, including most viruses (such as the Herpes family of viruses and human papillomavirus), some bacteria (including Salmonella and Mycobacteria), some yeast and fungi (such as Cryptococcus and Candida), and some parasites (such as Toxoplasma and Cryptosporidia).

Question 17

Immunologic consequences of destruction of CD4+ lymphocytes by HIV

Effect on Ab production:

Answer 17

Disordered antibody production. Loss of CD4 lymphocyte activity causes a reduced ability to make antibodies against new antigens, especially (but not only) protein antigens.

Question 18

Immunologic consequences of destruction of CD4+ lymphocytes by HIV

What do Abs do?
What does disregulation of Ab production lead to?

Answer 18

Antibodies defend against extracellular organisms, especially encapsulated bacteria like Streptococcus pneumoniae and Hemophilus influenza.

Disregulation of antibody production allows for overproduction of non-specific antibodies.

Question 19

Immunologic consequences of destruction of CD4+ lymphocytes by HIV

How is this detected?
How does this affect the diagnosis?
What diseases may be caused by Ab overproduction?

Answer 19

This can be detected as a polyclonal gammopathy.

It complicates the diagnosis of illnesses for which antibody tests or changes in antibody titers are the main diagnostic method.

Antibody overproduction may cause disease as well, such as in immune thrombocytopenia of HIV or hypercoaguable states.

Question 20

What is neutropenia?
What causes severe neutropenia?
What does this increase susceptibility to?

Answer 20

As a result of bone marrow failure in late HIV disease, or because of toxicities of anti-infective or anti-cancer therapies, severe neutropenia (neutrophil counts less than 500 cells/mm) may also occur and contribute to immunosuppression.

This would increase susceptibility to bacterial infections including Staphlococcus and Pseudomonas, and to fungi such as Aspergillus.

Question 21

Immune Response and Host Factors
Antibody response

Effect of early abs on virions:
When do neutralizing abs develop?

Answer 21

1. Early antibodies have no effect on virions but are convenient for testing
2. Neutralizing antibodies develop later during infection

Question 22

Immune Response and Host Factors
Antibody response

What is the effect in some primate models?
Possible protect effect of gp120 vaccine in humans:

Answer 22

Protective in some primate models

1) demonstrated by antibody infusion in primates challenged with SIV or SHIV.
2) protection of two chimps with gp120 vaccine.

Possible protective effect of a gp120 vaccine in humans.
1) gp120 mutates rapidly, escaping the effect of neutralizing antibodies produced by the host.

Question 23

Immune Response and Host Factors
Cellular immune response

What is cytotoxic CD8 lymphocytes activity evidence of early in infection?

What correlates with slower disease progression?

Answer 23

Cytotoxic CD8+ lymphocyte activity is evidence of anti-HIV cytotoxic T-lymphocyte (CTL) activity early in infection

Early recognition of HIV antigens by CD4 and CD8 lymphocytes (leading to in vitro proliferation) correlates with slower disease progression.

Question 24

Immune Response and Host Factors
Cellular immune response

What does frequency of CD8+ lymphocytes with cytotoxic activity against HIV envelope antigens in early infection inversely correlate with?

What allows for viral escape from cytotoxic T Cells?

Answer 24

Frequency of CD8+ lymphocytes with cytotoxic activity against HIV envelope antigens in early infection inversely correlates with plasma HIV RNA levels and with rates of CD4 lymphocyte decline.

Rapid mutation of cell service antigens also allows for viral escape from cytotoxic T-lymphocytes

Question 25

Immune Response and Host Factors
Cellular immune response

What is associated with faster or slower AIDS-free survival?
What does this indicate?
What may HLA molecules be important in?

Answer 25

Certain HLA B*35 types are associated with faster or slower AIDS-free survival, indicating a genetic component among determinants of disease progression.

Perhaps HLA molecules are important in the effectiveness of immune cellular recognition of HIV antigens, associated with differences in HLA class I molecules.

Question 26

Immune Response and Host Factors
Host cell susceptibility

Mutations in chemokine receptors:

Answer 26

Mutations in chemokine receptors, co-receptors for HIV on monocytes

CCR5 32 base pair deletion mutation

• Homozygotes resistant to infection
• Heterozygotes have slowly progressing disease

Question 27

Immune Response and Host Factors
Host cell susceptibility

Mutations in chemokines:

Answer 27

SDF-1, natural ligand of CXCR4, the HIV co-receptor of lymphocytes
- Persons with mutations may have slowly progressing disease

Question 28

Clinical course of HIV-1 infection in adolescents and adults

How long from diagnosis to AIDS defining illness without any treatment?

Answer 28

Without antiretroviral treatment or opportunistic infection prophylaxis, median time to an AIDS defining illness in developed countries was 10 years, and median overall survival with HIV infection was 11 years. Survival may be shorter in less developed nations, where many persons with HIV die of tuberculosis.

Question 29

Acquisition of HIV infection (mucosal [usually sexual] or parenteral)

What is the virus carried on? From, to where?
Replication where?
What does the next tier of replication in GALT produce? What else does it do?

Answer 29

Virus carried on dendritic cells from mucosal surface to regional lymph nodes

Replication in regional lymph nodes

Next tier of replication in gut-associated lymphoid tissue produces large amount of virus and rapidly destroys large numbers of CD4 cells including memory cells (in primate models)

Question 30

Acute Retroviral Syndrome (seroconversion syndrome) corresponds to:

What occurs in an uncertain proportion of individuals?
HIV ab tests:
What is initial high level of viremia coincident with?
What does the height of the viremia (plasma HIV RNA levels) during seroconversion predict?

Answer 30

Acute Retroviral Syndrome (seroconversion syndrome) corresponds to the intense virema

a) fever, adenopathy, rash, oral ulcers, neurologic symptoms and signs, sometimes immunosuppression, occurs in an uncertain proportion of individuals (perhaps as many as 80%) following HIV infection
b) Patients have negative or indeterminate HIV antibody tests, but high levels of HIV RNA in the plasma (or high levels of HIV DNA in cells)
c) Initial high level of viremia coincident with seroconversion. CD4+ lymphocyte count in the peripheral blood transiently falls from normal.

The height of the viremia (plasma HIV RNA levels) during seroconversion predicts the long term outcome of the infection!

Question 31

How long is the window between infection and positive screening?

Answer 31

Window period (2 weeks to 6 months) between acquisition of infection and a positive screening and confirmatory antibody test.

Question 32

Asymptomatic HIV

What happens to the level of virus in the plasma after acute retroviral syndrome?

In what tissue is HIV detected?

Answer 32

After the acute retroviral syndrome, the level of virus in the plasma decreases and stays fairly level at ‘set point.’

Most HIV is replicating in lymphoid tissue, and virus is spilling out into the blood plasma where it is detected.

Question 33

Asymptomatic HIV

How is replication and CD4+ lymphocyte destruction during latency?

What is predictive of long term outcome?

Immunologically normal above what CD count?

Answer 33

During this period of clinical latency, viral replication and CD4+ lymphocyte destruction is rapid but a steady state is maintained.

The set point (level of plasma HIV RNA) is also strongly predictive of the long term outcome of the infection.

For practical purposes, a person with a CD4 count above 500-600 may be immunologically normal.

a) no symptoms or persistent generalized lymphadenopathy (PGL).
b) May last many 5-10 or more years

Question 34

Symptomatic HIV

When is disease more severe?
Mild immunosuppression:
Moderate immunosuppression:

Answer 34

Disease with usual pathogens may be more frequent or more severe among persons with CD4 counts below 500-200.

CD4 500-350: mild immunosuppression.
CD4 350-200 moderate immunosuppression.

Question 35

Symptomatic HIV

Other diseases due to mild-moderate immunosuppression:

Due to moderately impaired cell-mediated immunity:

Answer 35

Some conditions are neither severe nor life threatening. They are often caused by usual pathogens but disease may be more frequent of more severe because of the mild-moderate immunosuppression. Examples include:
Seborrheic dermatitis, folliculitis, pneumococcal pneumonis, varicella zoster, sinusitis, cervical intraepithelial neoplasia.

Other conditions may be severe or suggestive of moderately impaired cell-mediated immunity. :::Examples include:
Oral candidiasis and oral hairy leukoplakia (due to Epstein-Barr virus)

Question 36

AIDS-defining conditions

What happens after many years?
What CD4 count is advanced immunosuppression?
CDC definition of AIDS:

Answer 36

After many years, for reasons that are not known, the amount of virus in the plasma increases more and more rapidly, the number of CD4+ lymphocytes falls more and more rapidly, and clinical disease occurs.

CD4 count below 200 is advanced immunosuppression. Patients are susceptible to serious and life threatening diseases due to opportunistic pathogens.

1) The CDC case surveillance definition, used to track the epidemic rather than for clinical purposes, considers an HIV infected person with a CD4+ lymphocyte count or 200/cu mm or less to have AIDS, regardless of the presence of symptoms or an AIDS defining condition.
2) A CD4 count below 50 represents advanced immunosuppression, when the most serious of opportunistic infections are most likely and when untreated survival is likely to be short.

Question 37

Rapid progressors

Definition:
How rapidly do they acquire AIDS?
Die?

Answer 37

Some persons have severe acute retroviral syndrome with very high plasma HIV RNA levels which never decline. They experience rapid falls in their CD4+ lymphocyte count. They develop AIDS-defining illnesses within 1-2 years and die within 2-3 years.

Question 38

Long term non-progressors:
%?
What are controllers?
Elite controllers?

Answer 38

Long term non-progressors are persons with HIV infection, who are clinically and immunologically normal, who have normal and stable CD4+ lymphocyte counts despite HIV infection for a minimum of 7-10 years (contrast with long term survivors, above).

About five percent of adults with HIV infection may be long term non-progressors.

Most have very low amounts of virus (called “controllers”), and some have plasma HIV RNA levels below the limit of quantification or detection (“elite controllers”). Over additional years, some of these persons develop immune deficiency and become ill.

Question 39

What do most long term non-progressors have high levels of?
What do some have deletions of?
What is defective HIV?

Answer 39

Most long term non-progressors have very high levels of anti-HIV CTL activity

Some of these patients are heterozygotes for the CCR5 deletion mutation

Rarely, patients are infected with a defective HIV, such as transfusion recipients in Australia infected with a nef-deletion mutant.

Question 40

Schematic of natural history of HIV infection of adults (original paradigm)

What does effective antiretroviral therapy do?

Answer 40

Effective antiretroviral therapy prevents viral replication, and maintains or allows replenishment of CD4 cells, and reverses or prevents AIDS.

Question 41

Emerging view of HIV natural history

What can early aging of the immune system produce?
Risk is associated with:
What can anti-retroviral therapy do?

Answer 41

Emerging view of HIV natural history: early aging of the immune system because of chronic immune activation can produce premature vascular disease (atherosclerosis) and premature non-AIDS related cancers in persons with “safe” CD4 lymphocyte counts.

The risk of these disorders may be associated with increased levels of certain soluble markers of inflammation (IL-6, high sensitivity C reactive protein, and others).

Antiretroviral therapy can slow this process, but may not prevent it entirely.

Question 42

Spontaneous cure of HIV

Answer 42

There are no well documented cases of spontaneous cure of HIV infection in adults.

A small number of perinatally exposed infants have been transiently positive by HIV DNA tests on several occasions, and then have gone on to have negative HIV DNA tests, negative antibody tests, and be clinically and immunologically normal for up to 5 years.

Some authorities consider this evidence of spontaneous cure, others believe it is represents laboratory error.

Question 43

The Berlin Patient:

Answer 43

One HIV patient on antiretroviral therapy developed acute leukemia, and underwent a stem cell transplant with a 10-antigen matched, CCR5 homozygous deficient donor in Germany. The leukemia relapsed, and the patient underwent a second transplant from the same donor. This patient remains HIV virus negative in plasma and rectal biopsy about 2 years post transplant, without any post-transplant antiretroviral therapy. He remains alive and healthy off antiretrovirals. Many consider him the first cure.

Question 44

Drugs are available that effect several different points in the viral replication cycle

Attachment:
Fusion:

Answer 44

Attachment (CCR5 binding inhibitor) and fusion (gp41 inhibitor)

Question 45

Drugs are available that effect several different points in the viral replication cycle

RT-I:
What transfers inhibitors?
Potease Inhibitors:

Answer 45

Reverse transcriptase inhibitors (both nucleoside analogues and non-nucleoside analogues)

Integrase strand transfer inhibitors

Protease inhibitors

Question 46

What suppresses plasma viral loads several logs, to levels below the limit of quantification of current assays?

What does suppression allow the host to do?

What prevents drug resistance?

Answer 46

Potent combinations of ≥3 antiretroviral drugs can suppress plasma viral loads several logs, to levels below the limit of quantification of current assays (

Question 47

What does partial suppression allow?

When does partial suppression occur?

What % of the doses must the patients take to avoid emergence of drug resistance?

Answer 47

Partial suppression allows for selection of drug resistant mutants by the drug regimen.

Partial suppression occurs when an inadequate regimen is prescribed, or when the patient does not take enough of their prescribed medication.

For some combinations, patients must take more than 95% of doses to avoid emergence of drug resistance. Other combinations are more forgiving.

Question 48

How is the effectiveness of modern combination antiretroviral therapy evident?

The emerging target for therapy is:

Answer 48

The effectiveness of modern combination antiretroviral therapy is evident in the decrease in new diagnoses of AIDS (ie progression of HIV to severe immunosuppression) and HIV/AIDS-related deaths in the US since late 1995.

The emerging target for therapy is to reduce immune activation and better preserve lymphocyte number and function. This leads to interest in initiating antiretroviral therapy earlier. Earlier starts of ARVs is supported by observational data, but to date there are no randomized clinical trials to inform the decision as to when to start treatment.

Question 49

What is there emerging interest in?

Our current challenges in regard to HIV treatment:

Answer 49

There is emerging interest in reducing the risks of vascular disease, bone loss, and non-AIDS associated malignancies to further improve clinical outcomes.

Our current challenges in regard to HIV treatment: balancing the virologic benefits with the need for excellent adherence and the risk of toxicity and drug resistance.

Question 50

What is used to reduce HIV transmission?

Answer 50

Use of antiretroviral drugs to reduce HIV transmission.

Question 51

Perinatal transmission definition:

What reduces HIV transmission to fetus? (2)

Answer 51

Perinatal transmission: transmission occurs mostly during labor and delivery, less so in utero, and during “mixed” breast feeding.

1. Antiretroviral therapy during labor greatly reduces HIV transmission
2. Elective Ceasarian section (surgical delivery) before onset of labor reduces HIV transmission

Question 52

Current US standard for Pregnant Women

During 2nd and 3rd trimesters of pregnancy:

During labor:

Answer 52

Combination antiretroviral therapy during 2nd and 3rd trimesters of pregnancy

IV zidovudine (single drug) during during labor

Question 53

Current US standard for Pregnant Women

To newborn for first 6 weeks of life:

What if viral load not suppressed on therapy by 36 weeks of pregnancy

Answer 53

Oral zidovudine (single drug) to newborn for first 6 weeks of life

Elective Ceasarian section if viral load not suppressed on therapy by 36 weeks of pregnancy

Question 54

Health care worker exposure and Post Exposure Prophylaxis (PEP):

Answer 54

Use of combination antiretroviral therapy for one month following needlestick exposure or severe mucosal exposure to HIV containing blood or body fluids.

Question 55

Life style exposure Post Exposure Prophylaxis (PEP):

Answer 55

Option of providing persons with one month of combination antiretroviral therapy to reduce risk of acquisition after an unsafe sexual encounter

Question 56

Pre-exposure prophylaxis: three recent randomized controlled trials

High risk risk men having sex with men:
High risk women:
Coital use of topical vaginal antiretroviral (tenofovir gel):

Answer 56

Daily use of combination antiretroviral therapy in high risk men having sex with men reduced risk of HIV acquisition about 40%

Daily use of combination antiretroviral therapy in high risk women did not reduce HIV acquisition

Coital use of topical vaginal antiretroviral (tenofovir gel) before and after intercourse reduced HIV acquisition by women about 40%

Question 57

Treatment of HIV infected persons

Reduce transmission with discordant couples:

Answer 57

Randomized trial showed 96% reduction of transmission among discordant heterosexual couples when the infected partner was on ARVs.

Question 58

Treatment of HIV infected persons

Community Viral Load:

Answer 58

Some observational data interpreted to suggest that with increased levels of effective treatment in the community, the overall amount of virus decreases in the community with a reduction in HIV transmission

Question 59

Treatment of HIV infected persons

Test and Link to Care and Treatment:

Answer 59

Observational and randomized trials to see if aggressive testing and treatment of HIV infected persons will reduce transmission in communities (like the Bronx and Washington DC!)