What is Antiretroviral Therapy? – Flashcards

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What does ARTs Do?
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ART substantially reduces the amount of replicating virus in the body. Results in lowered viral load Some restoration of CD4 T-cell counts
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what is HAART
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highly active antiretroviral therapy
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How do ARTs work?
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inhibit the virus without inhibiting the normal function of the cell.
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What are the 5 classes of ARTS?
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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
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How do Entry Inhibitors work? Explain fusion and binding inhibitors.
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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).
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What impact might lack of CCR5 have on potential HIV infection?
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Much less likely to get HIV could get infected through CXCR4 (unlikely)
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What are nucleotides?
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the building blocks of RNA and DNA Adenine Thynime Cytosine Guanine
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Can Reverse Transcriptase make errors?
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sometimes inserts wrong nucleotides causing mutations
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what are nucleoside reverse transcriptase inhibitors?
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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
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What is a non-nucleoside RT inhibitor?
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NNRTI: Non-nucleoside reverse transcriptase inhibitor binds reverse transcriptase to stop reverse transcription (BINDS TO RT MITTEN)
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What does Integrase Inhibitors Do?
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Binds to integrase enzyme to block integration. Without integration,the virus cannot complete the life cycle.
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How do protease inhibitors work?
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Binds to protease enzyme to prevent viral maturation. Immature viruses cannot infect new cells.
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What does Salvage Therapy include?
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1 binding entry inhibitor 1 fusion entry inhibitor
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Most commonly used drugs
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13 nucleoside reverse transcriptase inhibitors 6 non-nucleoside reverse transcriptase inhibitors 11 protease inhibitors 2 integrase inhibitors 3 multi-class combination drugs
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Explain phase 1 of approving drugs
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Phase I: evaluate safety of a drug and side effects in 20-80 individuals.
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Explain phase 2 of approving drugs
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Phase II: Determine effectiveness and further safety in 100-300 individuals
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Explain phase 3 of approving drugs
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Phase III: Confirm effectiveness, monitor side effects, compare to current treatments, and collect additional information on safe use in 1,000-3,000 individuals
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Explain phase 4 of approving drugs
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FDA approval and Phase IV: seek additional info on drug's risk, benefits, and optimal use
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How do we measure HIV disease progression?
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-Measure the number of viruses in the blood B. Measure the number of CD4+ T-cells
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What are two ways to monitor HIV infection?
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HIV Viral Load CD4T Cell count
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What are four goals of Antiretroviral therapy?
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Reduce the viral load Reduces transmission to sexual partners Improve the CD4 T cell count Improves immune response to pathogens other than HIV
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How do we know ARTs are working?
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Increase in CD4T Decrease in Viral Loads
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What do undetectable Viral Loads tell us?
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The drugs are working to substantially reduce the amount of actively replicating virus in the blood
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What do undetectable viral loads not tell us?
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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
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What are two different kinds of CD4T cells?
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Actively Replicating Cells Resting Cells
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What are Actively Replicating Cells
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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.
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What are Resting Cells
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Resting cell: occurs when a cell has not been activated to expand and it sits quiescently.
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What kind of CD4T cells does HIV infect?
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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."
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Why Cant HIV be cured with ART Alone?
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ART only inhibits replicating virus, so latent virus hiding in cells are not eliminated and therefore HIV cannot be cured with ART alone
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What is HAART? when did it begin? What are HAARTS goals?
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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)
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When was- Identified infectious agent, but there was no treatment, no cure.
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1981-1986: 1981-1986: Diagnosis meant certain death within months to years
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Year that AZT-first hope (NRTI) was discovered Viral loads decreased, but resistance develops within months Still no good treatment options
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1987
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what year were we Building up reverse transcriptase and protease inhibitors?
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1988-1995
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HAART discovered In what year?
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1996 for the first time disease could be controlled
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When was Trizivir-first triple therapy single pill made?
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2000
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name 5 bad things about ARTs.
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Cost, Adherence, Access, Side effects, drug resistance
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What is seridiscordinate ?
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pertaining to a relationship with one HIV-positive partner and one HIV-negative partner.
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What does the WHO guidelines say about CD4T cell counts to start ARTs?
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CD4+ T-cell count ≤500 cells/mm3 advanced clinical disease Pregnancy Co-infection with TB or HBV or serodiscordant partner
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What does the DDH (USA) guidelines say about starting ARTs?
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All HIV-infected individuals History of an AIDS defining illness Pregnancy History of HIV-associated nephropathy Hepatitis B co-infection requiring HBV treatmen
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DDH (USA) guidelines/recommendations for starting ARTs in respect to CD4T cell count?
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≤350 cells/mm High recommendation ≤500 cells/mm recommended >500 cells/mm up to Doc and patient
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What happens if you start ARTs at actue stage of infection?
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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
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What happens when you start ARTs at Diagnosis?
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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
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Why do people wait to start ARTs?
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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
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How expensive is ART and what are programs that help care people pay?
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$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)
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What is First Line therapy?
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Most effective and/or most widely available drug treatment regimen ($115/year)
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What is Second Line therapy?
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Alternative treatment used when the first-line therapy fails or is intolerable ($330)
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What is salvage therapy?
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Salvage therapy: Used when most reverse transcriptase and protease inhibitor combinations have failed (>$1500/ year)
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What are two ways to get ARTs to low income countries?
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Mobile Clinics Group Care (groups come together to pool in money to travel to drugs)
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What is PEPFAR? how many people are using its source? when was it established ?
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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
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the Global Fund fights what three diseases and how many people are using it?
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AIDS TUBERCULOSIS MALARIA~6.6 million individuals obtain ARTs through this funding source
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Define Evolution
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change in a genetic trait (the color of the moth) over generations
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Define Natural Selection (who proposed this idea and when)
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Process by which beneficial traits become more common and detrimental traits become less common or die out (Charles Darwin 1859)
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Describe how HIV evolves?
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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
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How many pairs of nucleotides does HIV have in its Genome
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9,800
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During each round of replication how many nucleotides are mutated?
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1 NOTE: every nucleotide in the genome is mutated every day
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What are quasispecies?
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Each person has thousands of slightly different viruses in their body-every body makes slightly diff proteins
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What is selection pressure? and two kinds of it?
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Anything that reduces reproductive success in HIV or any living organism; puts pressure on survival Drug pressure/Immune pressure
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How does HIV develop resistance to antiretroviral drugs?
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The virus mutates
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Why is HIV prone to drug resistance?
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HIV replication is very error prone HIV replicates quickly
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What percentage of HIV infected people become resistant to ARTs in 8 years?
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30%
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Name two methods to prevent resistance?
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Combination therapy Adherence
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What are some ways to monitor adherence?
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Pill counts, text message reminders, monitor drug levels in blood
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How can one monitor drugs without drug resistance testing? (because it costs a lot of money )
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Monitor CD4T cells counts Monitor symptoms
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What is PrEP?
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Taking a pill when you are HIV- to prevent HIV infection
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When was PrEP FDA approved?
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July 2012
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PrEP is a comination of what two drugs? and what is the name of this combination?
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Emtricitabine and Tenotovir=Truvada
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PrEP is what kind of inhibitor?
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NRTI (emtricitabinea and tenotovir) NOTE:safe/tolerable may prevent latency
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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?
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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
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FEMPPrEP? HIV-or+? why bad results? what countries involved?
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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
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TDF2 trial (PrEP trial) = Work? percentage of reduction of HIV? what kind of sexual orientation in trial? What was lower in this trial?
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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)
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In the Partners PrEP (PrEP) trial= what % of decrease in HIV? what kind of orientation involved? Countries involved?
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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
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How much greater is the chance of transmission through anal than vag?
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20 times greaters
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Thinking in terms of receptive and insertive from high risk to low risk rate the 5 types of sex
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receptive anal, receptive vag, insertive anal, insertive vag, oral
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how is anal tissue different than vag tissue (2)?
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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
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no infections occurred in studies when HIV+ partners VL was less than what ____ copies/ml plasma
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1,500
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when is acquiring HIV at highest risk?
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acute infection
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In early 2000's San Francisco implemented "test and treat" strategies to do what?
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increase identification of HIV individuals and link them to health care
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Median time from diagnosis to initiation of ART + decreased from ___ months in 2004 to ___ months in 2010
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27,5
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What is community viral load?
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mean viral load among a given population
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what are two findings in the San Fransisco study?
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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
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Explain HPTN052 (TSAP)
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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
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what was HTPN052 first goal and second goal?
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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
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what was the p value in HTPN052
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p<0.0001
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Early ART that suppresses viral replication led to a ____% reduction of sexual transmission of HIV in serodiscordant couples
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96
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Early initiation of ART reduced by ___the number of HIV-related clinical visits
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41%
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Approximately ___% of men worldwide are circumcised Approximately ___ %of men in the U.S. are circumcised
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30% , 79%
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Male circumcision was ____% efective in preventing heterosexual transmission in men
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50-60
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why does circumsicion reduce HIV?
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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
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What are Langerhan cells?
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Langerhans cells (LC) which can carry virus through epidermis to CD4 T cells
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What is a microbiome?
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aggregate of microorganisms that reside on the skin, oral mucosa, eyes and gastrointestinal tract.
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What is PrePex?
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surgical device for male circ.
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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
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80, 20
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what country is furthest alone in getting circs and by what percent?
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Kenya 63%
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What are two male circ misconceptions?
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Need to avoid giving people a false sense of security May increase risky behavior
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Approximately how many men do you think had been circumcised in the 14 priority countries between 2008-2013?
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6,000,000
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