question

What does ARTs Do?

answer

ART substantially reduces the amount of replicating virus in the body. Results in lowered viral load Some restoration of CD4 T-cell counts

question

what is HAART

answer

highly active antiretroviral therapy

question

How do ARTs work?

answer

inhibit the virus without inhibiting the normal function of the cell.

question

What are the 5 classes of ARTS?

answer

1. Entry inhibitors A. Binding inhibitors B. Fusion inhibitors 2. Nucleoside reverse transcriptase inhibitor 3. Non-nucleoside reverse transcriptase inhibitor 4. Protease inhibitor 5. Integrase inhibitor

question

How do Entry Inhibitors work? Explain fusion and binding inhibitors.

answer

Prevent the virus from entering the cell Mechanisms 1. Bind to virus to prevent fusion of virus with the cell (aka: fusion inhibitor). 2. Bind to cell receptor (CCR5) to block virus from binding to the cell (aka: binding inhibitor).

question

What impact might lack of CCR5 have on potential HIV infection?

answer

Much less likely to get HIV could get infected through CXCR4 (unlikely)

question

What are nucleotides?

answer

the building blocks of RNA and DNA Adenine Thynime Cytosine Guanine

question

Can Reverse Transcriptase make errors?

answer

sometimes inserts wrong nucleotides causing mutations

question

what are nucleoside reverse transcriptase inhibitors?

answer

NRTI: Nucleoside reverse transcriptase inhibitor-false nucleotide that stops reverse transcription. (BINDS TO DNA STRAND THINKS RT IS DONE) A nucleoside is a chemical precursor of a nucleotide

question

What is a non-nucleoside RT inhibitor?

answer

NNRTI: Non-nucleoside reverse transcriptase inhibitor binds reverse transcriptase to stop reverse transcription (BINDS TO RT MITTEN)

question

What does Integrase Inhibitors Do?

answer

Binds to integrase enzyme to block integration. Without integration,the virus cannot complete the life cycle.

question

How do protease inhibitors work?

answer

Binds to protease enzyme to prevent viral maturation. Immature viruses cannot infect new cells.

question

What does Salvage Therapy include?

answer

1 binding entry inhibitor 1 fusion entry inhibitor

question

Most commonly used drugs

answer

13 nucleoside reverse transcriptase inhibitors 6 non-nucleoside reverse transcriptase inhibitors 11 protease inhibitors 2 integrase inhibitors 3 multi-class combination drugs

question

Explain phase 1 of approving drugs

answer

Phase I: evaluate safety of a drug and side effects in 20-80 individuals.

question

Explain phase 2 of approving drugs

answer

Phase II: Determine effectiveness and further safety in 100-300 individuals

question

Explain phase 3 of approving drugs

answer

Phase III: Confirm effectiveness, monitor side effects, compare to current treatments, and collect additional information on safe use in 1,000-3,000 individuals

question

Explain phase 4 of approving drugs

answer

FDA approval and Phase IV: seek additional info on drug's risk, benefits, and optimal use

question

How do we measure HIV disease progression?

answer

-Measure the number of viruses in the blood B. Measure the number of CD4+ T-cells

question

What are two ways to monitor HIV infection?

answer

HIV Viral Load CD4T Cell count

question

What are four goals of Antiretroviral therapy?

answer

Reduce the viral load Reduces transmission to sexual partners Improve the CD4 T cell count Improves immune response to pathogens other than HIV

question

How do we know ARTs are working?

answer

Increase in CD4T Decrease in Viral Loads

question

What do undetectable Viral Loads tell us?

answer

The drugs are working to substantially reduce the amount of actively replicating virus in the blood

question

What do undetectable viral loads not tell us?

answer

If the virus is in other compartments of the body like the lymph nodes or intestines but is undetectable in the blood 2. If the virus is present below the limit of detection of the viral load assay (some assays cannot detect below 400 copies of virus/ml of blood, some can detect as little as 50 copies/ml) 3. Anything about the latent virus hiding in resting cells

question

What are two different kinds of CD4T cells?

answer

Actively Replicating Cells Resting Cells

question

What are Actively Replicating Cells

answer

Actively replicating cell: occurs when the immune system detects a foreign antigen and signals CD4+ T-lymphocytes to expand so they can provide more help.

question

What are Resting Cells

answer

Resting cell: occurs when a cell has not been activated to expand and it sits quiescently.

question

What kind of CD4T cells does HIV infect?

answer

HIV preferentially infects actively replicating cells, but the cells can shut down to become resting after HIV integrates it's genome into the host genome. Virus in these resting cells is considered "latent."

question

Why Cant HIV be cured with ART Alone?

answer

ART only inhibits replicating virus, so latent virus hiding in cells are not eliminated and therefore HIV cannot be cured with ART alone

question

What is HAART? when did it begin? What are HAARTS goals?

answer

Combination therapy is also known as HAART Highly Active Anti-Retroviral Therapy Combination of 3 or more drugs from two different categories Began use in 1996 First long-term treatment option for HIV Goals: Reduce viral load to undetectable (HIV RNA in the blood) Reduce HIV transmission (lower viral load) Boost CD4+ T-cell counts in the blood (reduce opportunistic disease)

question

When was- Identified infectious agent, but there was no treatment, no cure.

answer

1981-1986: 1981-1986: Diagnosis meant certain death within months to years

question

Year that AZT-first hope (NRTI) was discovered Viral loads decreased, but resistance develops within months Still no good treatment options

answer

1987

question

what year were we Building up reverse transcriptase and protease inhibitors?

answer

1988-1995

question

HAART discovered In what year?

answer

1996 for the first time disease could be controlled

question

When was Trizivir-first triple therapy single pill made?

answer

2000

question

name 5 bad things about ARTs.

answer

Cost, Adherence, Access, Side effects, drug resistance

question

What is seridiscordinate ?

answer

pertaining to a relationship with one HIV-positive partner and one HIV-negative partner.

question

What does the WHO guidelines say about CD4T cell counts to start ARTs?

answer

CD4+ T-cell count ≤500 cells/mm3 advanced clinical disease Pregnancy Co-infection with TB or HBV or serodiscordant partner

question

What does the DDH (USA) guidelines say about starting ARTs?

answer

All HIV-infected individuals History of an AIDS defining illness Pregnancy History of HIV-associated nephropathy Hepatitis B co-infection requiring HBV treatmen

question

DDH (USA) guidelines/recommendations for starting ARTs in respect to CD4T cell count?

answer

≤350 cells/mm High recommendation ≤500 cells/mm recommended >500 cells/mm up to Doc and patient

question

What happens if you start ARTs at actue stage of infection?

answer

May reduce CD4+ T-cell depletion in the intestinal mucosa-a site of early HIV replication that diminishes the immune system Decrease transmission during peak viremia by reducing peak viral load Most diagnoses occur after acute infection, so treating here is not possible most of the time

question

What happens when you start ARTs at Diagnosis?

answer

May provide some benefit by reducing CD4+ T-cell loss Reduces ongoing transmission risk This recommendation is for public health rather than personal health of the HIV+ individual

question

Why do people wait to start ARTs?

answer

Cost Once you start you can't stop-for life Sooner you start the sooner drug resistance may severely hamper drug options Side effects-getting better with new generations of ART High levels of adherence are required: patient needs to be ready Increase in life expectancy not much greater if you start at <200 cells/mm 3 than <500 cells/mm 3 Need to prioritize use of limited antiretroviral drug supply

question

How expensive is ART and what are programs that help care people pay?

answer

$2-5,000 a month IN US $115 per year in low income countries Medicare/Medicade Affordable Health Care act Ryan White Health Care Act (grants to hospitals) AIDS drug assistance program (ADAP)

question

What is First Line therapy?

answer

Most effective and/or most widely available drug treatment regimen ($115/year)

question

What is Second Line therapy?

answer

Alternative treatment used when the first-line therapy fails or is intolerable ($330)

question

What is salvage therapy?

answer

Salvage therapy: Used when most reverse transcriptase and protease inhibitor combinations have failed (>$1500/ year)

question

What are two ways to get ARTs to low income countries?

answer

Mobile Clinics Group Care (groups come together to pool in money to travel to drugs)

question

What is PEPFAR? how many people are using its source? when was it established ?

answer

President's Emergency Plan for AIDS relief started in 2003 by president Bush Currently ~6.7 million individuals are obtaining ARTs through this funding source Some of this funding goes towards the Global Fund

question

the Global Fund fights what three diseases and how many people are using it?

answer

AIDS TUBERCULOSIS MALARIA~6.6 million individuals obtain ARTs through this funding source

question

Define Evolution

answer

change in a genetic trait (the color of the moth) over generations

question

Define Natural Selection (who proposed this idea and when)

answer

Process by which beneficial traits become more common and detrimental traits become less common or die out (Charles Darwin 1859)

question

Describe how HIV evolves?

answer

High error rate during reverse transcription (1 mutation at every nucleotide of RNA genome/day) High replication rate (10^10 viruses/day) (that's 10 billion!) **Mutations arise spontaneously (they are random)** The virus doesn't "think" and cannot make specific mutations by choice The virus only survives or does not survive

question

How many pairs of nucleotides does HIV have in its Genome

answer

9,800

question

During each round of replication how many nucleotides are mutated?

answer

1 NOTE: every nucleotide in the genome is mutated every day

question

What are quasispecies?

answer

Each person has thousands of slightly different viruses in their body-every body makes slightly diff proteins

question

What is selection pressure? and two kinds of it?

answer

Anything that reduces reproductive success in HIV or any living organism; puts pressure on survival Drug pressure/Immune pressure

question

How does HIV develop resistance to antiretroviral drugs?

answer

The virus mutates

question

Why is HIV prone to drug resistance?

answer

HIV replication is very error prone HIV replicates quickly

question

What percentage of HIV infected people become resistant to ARTs in 8 years?

answer

30%

question

Name two methods to prevent resistance?

answer

Combination therapy Adherence

question

What are some ways to monitor adherence?

answer

Pill counts, text message reminders, monitor drug levels in blood

question

How can one monitor drugs without drug resistance testing? (because it costs a lot of money )

answer

Monitor CD4T cells counts Monitor symptoms

question

What is PrEP?

answer

Taking a pill when you are HIV- to prevent HIV infection

question

When was PrEP FDA approved?

answer

July 2012

question

PrEP is a comination of what two drugs? and what is the name of this combination?

answer

Emtricitabine and Tenotovir=Truvada

question

PrEP is what kind of inhibitor?

answer

NRTI (emtricitabinea and tenotovir) NOTE:safe/tolerable may prevent latency

question

In the IPrEX trial what % of reduction was shown in HIV? What kind of population did the trial cover? countries included? Used for HIV- or HIV+? Work?

answer

iPrEX: 44% reduction in incidence of HIV MSM population PREP TRIAL Brazil, Equador, Peru, South Africa, United States, Thailand HIV- FTC/TDF (Truvada) Individuals enrolled received counseling on safer sex, HIV testing, condoms, treatment for STDs on a monthly basis In individuals who had detectable levels of drugs in plasma or blood cells has a 92-95% reduced risk of HIV infection Adherence makes a tremendous difference! WORKED

question

FEMPPrEP? HIV-or+? why bad results? what countries involved?

answer

FEMPrEP: stopped early due to lack of efficacy Higher-risk women HIV- Kenya, Tanzania, and South Africa FTC/TDF Among infected participants: reported adherence was 95%, pill count adherence was 88%, drug level testing adherence was 15-26% Among uninfected, adherence was slightly higher (24-35%) Overall low adherence reduced the power of this study to see a positive effect of once-daily FTC/TDF Does this indicate biological differences in effectiveness of PrEP with different routes of HIV transmission

question

TDF2 trial (PrEP trial) = Work? percentage of reduction of HIV? what kind of sexual orientation in trial? What was lower in this trial?

answer

TDF2 study: 62% reduction in incidence of HIV heterosexual men and women Botswana FTC/TDF Adherence based on drug levels in plasma was 50% in those infected and 80% in those uninfected. Among those infected, total plasma levels of drug were significantly lower (0.3ng/ml vs. 30ng/ml for TDF and 0.5ng/ml vs. 103ng/ml FTC) Decline in bone mineral density over 2 years (low to begin with in this population)

question

In the Partners PrEP (PrEP) trial= what % of decrease in HIV? what kind of orientation involved? Countries involved?

answer

PrEP trials: Partners PrEP Partners PrEP study: 67% reduction in HIV incidence with TDF and 75% with TDF/FTC Heterosexual serodiscordant couples (one person HIV+ and the other HIV-) Kenya and Uganda 31% of those infected had detectable drugs in their plasma vs. 82% of those not infected

question

How much greater is the chance of transmission through anal than vag?

answer

20 times greaters

question

Thinking in terms of receptive and insertive from high risk to low risk rate the 5 types of sex

answer

receptive anal, receptive vag, insertive anal, insertive vag, oral

question

how is anal tissue different than vag tissue (2)?

answer

Rectal lining is thinner (only one cell thick) and more fragile than vaginal lining ! Rectal lining has specialized cells which may facilitate infection by binding to HIV and transporting it to underlying CD4 24 + T cells

question

no infections occurred in studies when HIV+ partners VL was less than what ____ copies/ml plasma

answer

1,500

question

when is acquiring HIV at highest risk?

answer

acute infection

question

In early 2000's San Francisco implemented "test and treat" strategies to do what?

answer

increase identification of HIV individuals and link them to health care

question

Median time from diagnosis to initiation of ART + decreased from ___ months in 2004 to ___ months in 2010

answer

27,5

question

What is community viral load?

answer

mean viral load among a given population

question

what are two findings in the San Fransisco study?

answer

Efforts to increase HIV status awareness and engagement in treatment resulted in a 40% drop in "community viral load" Fall in community viral load is associated with a 30% decrease in new HIV infections

question

Explain HPTN052 (TSAP)

answer

for HIV+ people to not pass on to partners. treatment as prevention/Phase 3/two arm/RANDOMIZED HIV serodiscordant couples were randomly assigned at a 1:1 ratio to either early or delayed ART arm

question

what was HTPN052 first goal and second goal?

answer

Primary Goal: To test the effects of ART on the prevention of HIV transmission to uninfected partners ! Secondary Goal: To test whether the early initiation of ART reduced the number HIV-related clinical visits

question

what was the p value in HTPN052

answer

p<0.0001

question

Early ART that suppresses viral replication led to a ____% reduction of sexual transmission of HIV in serodiscordant couples

answer

96

question

Early initiation of ART reduced by ___the number of HIV-related clinical visits

answer

41%

question

Approximately ___% of men worldwide are circumcised Approximately ___ %of men in the U.S. are circumcised

answer

30% , 79%

question

Male circumcision was ____% efective in preventing heterosexual transmission in men

answer

50-60

question

why does circumsicion reduce HIV?

answer

Foreskin has a high concentration of cells susceptible to HIV-infection The penis shaft has more keratin (ﬁbrous protein in the skin) than the foreskin, so there is a lower likelihood of tearing Alteration in populations of commensal bacteria (microbiome) Reduction in the inﬂammation in the skin of the penis

question

What are Langerhan cells?

answer

Langerhans cells (LC) which can carry virus through epidermis to CD4 T cells

question

What is a microbiome?

answer

aggregate of microorganisms that reside on the skin, oral mucosa, eyes and gastrointestinal tract.

question

What is PrePex?

answer

surgical device for male circ.

question

Have a goal of circumcising ___% of men in these countries by 2015 and maintaining level for another 10 years Estimate ____% of new HIV infections can be averted

answer

80, 20

question

what country is furthest alone in getting circs and by what percent?

answer

Kenya 63%

question

What are two male circ misconceptions?

answer

Need to avoid giving people a false sense of security May increase risky behavior

question

Approximately how many men do you think had been circumcised in the 14 priority countries between 2008-2013?

answer

6,000,000

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