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94 Cards in this Set
- Front
- Back
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Pandemic - Definition
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Emergence of a disease new to the population that infects humans causing serious illness and that spreads easily
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Epidemic - Definition
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Disease that appears as new cases in a given human population, during a given period, at a rate that exceeds what is "expected" (local-MRSA, general-rabies, global-HIV, plague)
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Endemic - Definition
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Common diseases that occur at a constant rate in a population in a defined place or region (malaria in Africa)
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The 4 stages of evolution of HIV
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1. Emergence
2. Dissemination 3. Escalation 4. Stabilization |
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Emergence of HIV - Stage 1 of Evolution
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-HIV emerged from remote rural areas, where it was endemic at low levels
-Silent spread: industrialized countries among homosexual men; in developing countries among femal commercial sex workers and clients |
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Dissemination of HIV - Stage 2 of Evolution
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-HIV spreads quickly to various regions of the world
-Spread is secondary to migration/travel/change in cultural values in certain countries -Commercial sex industry grew prominently in some developing nations |
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Escalation of HIV - Stage 3 of Evolution
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-During the 1980s, infection spread to other high-risk individuals (IVDUs, heterosexual partners of patients with AIDS, blood transfusion recipients)
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Stabilization of HIV - Stage 4 of Evolution
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-Current phase in Australia, North America, Western Europe, Sub-Saharan Africa
-number of deaths due to HIV = number of new HIV infections -However, among certain populations, HIV infection is increasing |
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Molecular Etiology of HIV
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HIV is a member of the lentivirinae (lenti- means slow) subfamily of retroviruses. Lentiviruses are characterized by their indolent infectious cycle. HIV-1 is more common in the US and Europe. HIV-2 is more common in West Aftrican countries.
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Sexual Transmission of HIV
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Sexual transmission is the most common mode of transmission. The higher the viral load, the higher the risk of spreading the infection. There is a 0.1-3% chance of spreading HIV from anorectal intercourse and a 0.1-0.2% chance from receptive vaginal intercourse. Increased risk factors include ulcerative STD's, multiple sex partners, and sex partners of IVDU.
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Parenteral Transmission of HIV
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Parenteral transmission includes contaminated blood exposure from needle sticks, IV injection with used needles, receipt of blood products, or organ transplants. IVDU is a problem in developed countries as well as certain areas of SE Asia and Latin America. IVDU account for 25% of AIDS cases in the US. Needle exchange programs have been successful. The occupational risk of acquiring HIV from a percutaneous stick injury is approximately 0.3%.
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Perinatal Transmission of HIV
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Perinatal is the most common cause of pediatric HIV infection. Most infections occur during or near to the time of birth, but can occur during delivery or postnatal during breastfeeding. The risk of mother-to-child transmission is approximately 25% in the absence of breast-feeding and antiretroviral therapy. Other risk factors include prolonged rupture of membranes, genital infections during pregnancy, preterm delivery, vaginal delivery, low birthweight, illicit drug use during pregnancy, and high maternal viral load. Strategies to reduce perinatal transmission include no breastfeeding, C-section delivery, decreased maternal viral load, and treatment with zidovudine.
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Therapy for HIV-infected woman who is receiving HAART and becomes pregnant
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You should continue current HAART regimen if successfully suppressing viremia, except avoid use of EFV or other potentially teratogenic drugs in the first trimester and drugs with known adverse potential for the mother. HIV antiretroviral drug resistance testing is recommended if the woman has detectable viremia on therapy. In general, if woman requires treatment, antiretroviral drugs should not be stopped during the 1st trimester. Continue HAART regimen during intrapartum period (zidovudine given as a continuous infusion during labor while other antiretroviral agents are continued orally) and postpartum. Schedule cesarean delivery at 38 weeks gestation if plasma HIV RNA remains above 1,000 copies/mL near the time of delivery. Give the infant zidovudine for 6 weeks starting within 6-12 hours after birth.
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HIV Pathogenesis - HIV Virion
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The HIV virion is larger than 100 nm in diameter and is a sphere composed of an outer lipid bilayer membrane and a nucleocapsid with an internal dense cylindrical core.
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HIV Pathogenesis - The Virion Envelope
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The virion envelope consists of a lipid bilayer membrane. There are 72 projections from the outer membrane composed of the "outer" envelope protein (gp120) bound to the transmembrane protein (gp41). The envelope protein facilitates viral entry by binding to CD4, via gp120, and fusion to the cell membrane via gp41.
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HIV Pathogenesis - The Matrix Protein
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AKA the Gag protein (p17) surrounds the viral capsid. This protein is involved in the early stages of viral replication and plays a part in the formation and transport of the preintegration DNA complex into the nucleus host cell.
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HIV Pathogenesis - The Viral Capsid
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AKA the virion core consists of a major capsid protein (p24) and a diploid single-stranded RNA genome that contains 9 viral genes
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HIV Pathogenesis - The 3 Viral Enzymes
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-Protease, RT, and Integrase
1. HIV-1 protease has a primary function to cleave individual proteins from their respective precursors. It has to clease 8 different sites to process the gag, gag-pol precursors. This occurs primarily after the process of budding. 2. RT converts single-stranded RNA into double-stranded DNA. It is an important but limited target. It makes more mistakes than DNA polymerase in creating DNA. The DNA copy of the retroviral genome is called "provirus". It serves as a template for cellular DNA-dependent RNA polymerases after integration into the host genome. 3. Integrase is poorly understood, but thought to integrate retroviral genomes into host cell genome |
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HIV Pathogenesis - Chemokine Receptors CCR5 and CXCR4 and HIV
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Chemokines are polypeptide molecules produced and exported by cells as signals to activate or inhibit chemical processes in other cells. Chemokine receptors are specialized proteins functioning at the cell surface that enable chemokines to trigger intercellular processes without actually entering the cell. Chemokine binds receptor structure, which triggers a change in intracellular portions of receptor, which cause chemical signal to be generated inside the cell. The receptor signal is modified in the process. It must leave the cell surface to regenerate its initial state so it may return to cell surface and transduce a signal again. HIV entry into cells involves a complex interaction between CD4, the gp120 envelope protein and the chemokine receptor.
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Summary of CCR5 in HIV
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CCR5 receptor occurs on the surface of macrophages. Strains of HIV that infect macrophages more readily than CD4+ T-cells are known as Macrophage-Tropic HIV strains (M-Tropic). It is believed M-tropic strains establish HIV infection, while CD4+ T cell tropic strains are crucial to later stages of HIV disease. Persons who are homozygous for a genetic defect in the CCR5 receptor gene may be protected from HIV infection (HIV can't enter). Persons who are heterozygous for a genetic defect in CCR5 receptor gene have a lower rate of HIV disease progression.
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Summary of CXCR4 in HIV
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The CXCR4 receptor occurs on the surface of CD4+ T cells. Strains of HIV that infect CD4+ T-cells more readily than macrophages are known as T Cell Tropic HIV strains (T-Tropic)
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HIV Life Cycle (The Whole Thing)
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Free virus enters the blood during initial infection. As many as 10 million virions are produced daily.
Attachment/Entry - The viral envelope glycoprotein gp120 binds at two specific CD4 receptor sites on subpopulation of T-lymphocytes. After binding to the CD4 receptor, gp120 undergoes conformational changes which allow it to bind to the chemokine receptor. Entry into host cell (infection) by HIV-1 is followed by contents being emptied into cell. After entry, virion sheds envelope uncoating of the nucleocapsid and releases the complex of Gag and Pol proteins and the viral genome. Reverse Transcription - Reverse transcription located in the core of the virus is released and it converts RNA into double stranded DNA. Virus is transported to the nucleus Integration into host genome - Proviral DNA enters nucleus of host cell and integration of proviral DNA into host cell genome occurs using the integrase enzyme Transcription (early and late viral proteins) - When the infected cell divides, the host RNA polymerases "read" the viral DNA and transcribe it into mRNA Translation (precursor proteins) - synthesized into new viral proteins Assembly of the core structure - occurs at the cell membrane, beginning with the association of p17 with the cytoplasmic domain of the envelope protein gp4. Release (Budding) - Immature virus pushes out of the cell, taking part of the cell membrane Maturation - The precursor protein chains in the new viral particle are cut by the protease enzyme into individual proteins that combine to make the working virus. Note: 99% of viral replication occurs in CD4+ T-lymphocytes |
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Clinical Course of HIV
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Infection usually presents with an acute retroviral syndrome in40-90% of patients within 2 to 6 weeks after exposure. Common symptoms include fever, fatigue, night sweats, lymphadenopathy, myalgias, headache, nausea, and diarrhea. 40-80% will also present with a maculopapular rash involving the trunk. Other signs would be a high viral load and persistent decrease in CD4+.
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Review of HIV Pathogenesis
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The replicative process of HIV is continuous. Overall average rates of virion production is about 1 billion particles per day. Half of the viral load is cleared and replenished every 2 days or less.
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Diagnosing HIV
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HIV should be diagnosed by a rapid HIV test or an ELISA test. It can be confirmed by a Western blot or indirect immunofluorescence assay.
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Viral Load Testing
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The major test is HIV RNA PCR. There is a limit of detection that varies from 200-400 copies/mL for standard assays to 20-80 copies/mL for ultrasensitive assays. Undetectable load could be less than 50 copies/mL, but this does not mean the infection has been eradicated or that replication has stopped.
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Useful Prognostic Indicator of HIV
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30,000-50,000 copies/mL would be a poor prognosis
less than 5,000 copies/mL is a good prognosis A beneficial therapy would result in a log decrease of 0.5 log |
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Effective Antiretroviral Effect
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A 0.5 to 0.75 log decrease by 4-8 weeks after starting therapy and undetectable by weeks 12-16
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CD4+ lymphocyte count
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Gives indicatoin of immunologic destruction - it is the most important consideration to initiate antiretroviral therapy and give an indication of what types of OI's a patient is at risk of developing; when the CD4 count is less than 200, you should begin antiretroviral therapy
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Indications for Initiating Antiretroviral Therapy
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-History of AIDS-defining illness
-CD4 count less than 200 -Pregnant women -Persons with HIV-associated nephropathy -Persons coinfected with Hep B |
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Indications for Plasma HIV RNA testing
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-Initial evaluation of newly diagnosed HIV infection
-Prior to initiation of therapy -2-8 weeks after the start of therapy -Every 3-4 months in patients on therapy and stable -Clinical event or significant decline in CD4 T-cells |
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Indications for Drug Resistance Testing
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-Recommended for persons with HIV infection when they enter care regardless of whether therapy will be initiated immediately. If therapy is deferred, repeat testing at the time of initiation should be considered.
-Recommended to assist in selecting active drugs when changing antiretroviral regimens in cases of virologic failure -Recommended for all pregnant women -NOT advised for persons with HIV RNA <1,000 copies/mL b/c it is unreliable. |
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Special consideration with abacavir
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HLA-B*5701 Screening is recommended prior to initiation of abacavir-containing regiman, to reduce the risk of hypersensitivity reaction. If positive, patients should not be prescribed abacavir.
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Coreceptor Tropism Assay
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Should be performed whenever the use of a CCR5 inhibitor is being considered - this ensures that the virus is actually entering via CCR5 receptor
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What is the preferred NNRTI?
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Efavirenz
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In what population should you not use efavirenz?
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do not use during the 1st trimester of pregnancy or in those with high pregnancy potential
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What are the preferred PIs?
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atazanavir + ritonavir (qd)
darunavir + ritonavir (qd) fosamprenavir + ritonavir (bid) lopinavir + ritonavir (bid) |
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What is the preferred dual NRTI therapy?
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tenofovir + emtricitabine (Truvada)
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What is HAART therapy?
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1. Always consists of a NRTI backbone (2 drugs)
2. Always consists of either a NNRTI or PI |
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Strategies to Improve Adherence to Antiretroviral Therapy
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1. Establish readiness to start therapy
2. Provide education on medication dosing 3. Review potential side effects 4. Anticipate and treat side effects 5. Utilize educational aids including pictures, pillboxes, and calenders 6. Engage family and friends 7. Simplify regimens, dosing, and food requirements 8. Utilize team approach with nurses, pharmacists, and counselors 9. Provide accessible, trusting health care team |
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Main Guideline for Changing an Antiretroviral Regimen for Suspected Drug Failure
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Adding a single active drug to a failing regimen is not recommended. Use at least two new drugs or an entirely new regimen (try to include an agent with a different MOA than used previously).
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Which NRTI's are analogs for the same base?
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-zidovudine and stavudine are analogs of thymidine
-emtricitabine and lamivudine are analogs or cytosine |
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What is the one nucleoTIDE RTI and what are it's adavantages?
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tenofovir
It differs from NRTIs by requiring only 2 chemical steps, rather than 3, to become active inside the cell; it's unique chemical structure allows for it to stay longer in the cell |
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Trizivir
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abacavir, zidovudine, and lamivudine
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abacavir, zidovudine, and lamivudine
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Trizivir
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Epzicom
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abacavir and lamivudine
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Adverse Effects of abacavir
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Hypersensitivity reaction symptoms may include fever, rash, nausea, vomiting, malaise, or fatigue; respiratory symptoms such as sore throat, cough, and shortness of breath
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Elimination of abacavir
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Eliminated renally, don't use in patients with CrCl <50 mL/min
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Adverse Effects of didanosine
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-take 1/2 hour before or 2 hours after meals
-pancreatitis, peripheral neuropathy, nausea, lactic acidosis with hepatic steatosis is a rare but potentially life-threatening toxicity associated with use of NRTIs. |
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Atripla
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emtricitabine, tenofovir, and efavirenz
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emtricitabine, tenofovir, and efavirenz
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Atripla
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Truvada
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emtricitabine and tenofovir
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emtricitabine and tenofovir
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Truvada
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Adverse Effects of emtricitabine
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minimal toxicity, hyperpigmentation/skin discoloration
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Combivir
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lamivudine and zidovudine
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lamivudine and zidovudine
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Combivir
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Adverse Effects of stavudine
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lipodystrophy and hyperlipidemia
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Name the NRTIs
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abacavir
didanosine emtricitabine lamivudine stavudine tenofovir zidovudine |
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Important Adverse Effects of NRTIs
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-Lipodystrophy can be accumulation of visceral fat in the abdomen, dosocervical area and breasts; loss of subcutaneous fat in the face, exremities, and buttocks; or dyslipidemia. Risk factors include age over 40, history of AIDS for more than 3 years, CD4 count less than 100, BMI decrease, and white race.
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Resistance to NRTIs - Two mechanisms
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1. Impairment of the incorporation of the analogue into DNA
2. Removal of the analogue from the prematurely terminated DNA chain (thymidine analogue mutations) |
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Name the NNRTIs
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efavirenz
neviripine etravirine |
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Resistance to NNRTIs
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There is a high degree of cross-resistance within the class (no cross-resistance with NRTIs and PIs). The hydrophobic binding pocket is less well conserved than the binding area for NRTIs. A single mutation may cause high level resistance to one or all NNRTIs (except etravirine).
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Adverse Effects of efavirenz
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rash, false-positive cannabinoid test (marijuana), increased transaminases, vivid dreams early in therapy
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Dosing interval of etravirine
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twice daily
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Adverse Effects of nevirapine
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not recommended in patients with moderate-to-severe hepatic impairment; rash including Stevens-Johnson syndrome
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Name the Protease Inhibitors
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amprenavir
atazanavir fosamprenavir indinavir lopinavir + ritonavir (Kaletra) nelfinavir ritonavir saquinavir timpranavir darunavir |
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Important Adverse Effects of Protease Inhibitors
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GI producing diarrhea, abdominal pain, nausea, vomiting
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Resistance to PIs
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-consequence of AA substitutions that emerge either inside the substrate-binding domain of the enzyme or at distant sites
-directly or indirectly, these changes modify the number of points of contact between the PI and the protease, leading to reduced affinity -not all PI mutations impact all PIs |
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Dosing Interval for atazanavir
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once daily
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Dosing Interval for darunavir
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once daily
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Dosing Interval for fosamprenavir
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twice daily
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Kaletra
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lopinavir and ritonavir
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lopinavir and ritonavir
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Kaletra
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NRTI MOA
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Their structure mimics that of natural nucleosides. After undergoing phosphorylation, they compete with natural nucleosides and are preferentially incorporated into the new viral DNA by RT. Incorporation inhibits the elongation of the new DNA chain, thus halting replication.
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Protease Inhibitor MOA
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They block the maturation process by cleaving the polyprotein precursors that will generate the core proteins and enzymes of mature virions. Unlike RT inhibitors, the inhibition of protease impacts cell directly by halting production of new infectious virions. They have demonstrated activity in all stages of HIV.
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Fusion Inhibitors MOA
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They act by inhibiting the entry of HIV into the target cell (first step). They have potential action against drug resistant HIV strains, cause minimal adverse effects, and have a simplified dosing regimen.
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Name the Fusion Inhibitors
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enfuvirtide (Fuzeon)
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Dosing Interval of enfuvirtide
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subQ twice daily
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Chemokine Receptor Antagonist MOA
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designed to prevent HIV infection of CD4 cells by blocking chemokine receptor 5 (CCR5), a coreceptor necessary for HIV entry, from binding to HIV
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Name the Chemokine Receptor Antagonist
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maraviroc (Selzentry)
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Dosing Interval for maraviroc
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twice daily
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Integrase Inhibitor MOA
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inhibition of integrase prevents insertion of HIV DNA into the human DNA genome, thus blocking the ability of HIV to replicate
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Name the Integrase Inhibitor
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raltegravir (Isentress) - take with food to avoid nausea
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Prophylaxis of Pneumocystis pneumonia (PCP)
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Indication: CD4 count < 200
Use Bactrim 1 DS PO daily (or 3 times weekly) Alternative: Dapsone 100 mg qd |
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Prophylaxis of Toxoplasma gondii encephalitis
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Indication: CD4 count <100
Use Bactrim 1 DS PO daily Alternative: Dapsone |
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Prophylaxis of Mycobacterium avium complex (MAC)
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Indication: CD4 count<50
Use azithromycin 1,200 mg po once weekly |
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Use of Streptococcus pneumoniae vaccination in HIV
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Use if CD4 count is less than 200, can be given every 5 years
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Use of influenza A and B vaccination in HIV
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Use if CD4 count is less than 150; give annually
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Prophylaxis of Coccidioidomycosis
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Give if CD4 count is less than 250, use fluconazole 400 mg po daily
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Treatment of Toxoplasma gondii encephalitis
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Use pyrimethamine 200 mg one time, then 50-75 mg daily plus sulfadiazine 1000-1500 mg q6h plus leucovorin 10-25 mg PO daily
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Treatment of Candidiasis
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Use fluconazole 100 mg PO daily
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Treatment of Cryptococcal meningitis
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Use amphotericin B deoxycholate 0.7 mg/kg IV daily plus flucytosine 100 mg/kg PO daily in 4 divided doses for at least 2 weeks
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Treatment of Histoplasma capsulatum infections
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Use liposomal amphotericin B at 3 mg/kg IV daily; for maintenance use itraconazole 200 mg PO TID for 3 days, then BID
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Treatment of Aspergillosis
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Use voriconazole 6 mg/kg q12h for one day, then 4 mg/kg q12h IV, followed by voriconazole PO 200 mg q12h after clinical improvement
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