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Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
Antiretroviral Drugs
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Antiretroviral Drugs
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Antiretroviral Drugs

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    • 1. Antiretroviral Drugs
    • 2. HIV/AIDS <ul><li>Basics </li></ul><ul><li>HIV is a retrovirus </li></ul><ul><li>-Cell has RNA (instead of usual DNA) </li></ul><ul><li>When in host cell, the RNA, via the enzyme reverse tran- scriptase, makes DNA that gets into host DNA and replicates </li></ul>
    • 3. Body Fluids: Transmissible <ul><li>Blood </li></ul><ul><li>Semen </li></ul><ul><li>Vaginal secretions </li></ul><ul><li>Breast milk </li></ul><ul><li>Cerebral spinal fluid </li></ul><ul><li>Synovial fluid </li></ul><ul><li>Pleural & amniotic fluid </li></ul>
    • 4. Transmission Activities <ul><li>Unprotected sex-oral, anal, vaginal </li></ul><ul><li>Blood to blood-sharing needles, occupational exposure, fighting, tattooing, body piercing, transfusions </li></ul><ul><li>Mother to newborn-in utero, childbirth, breast feeding </li></ul>
    • 5. Body Fluids: Non-transmissible Important to know how you DON”T get HIV! <ul><li>Urine </li></ul><ul><li>Sweat </li></ul><ul><li>Saliva </li></ul><ul><li>Tears </li></ul><ul><li>Vomit </li></ul><ul><li>Mucous </li></ul><ul><li>Feces </li></ul>
    • 6. AIDS <ul><li>AIDS: Acquired Immunodeficiency Syndrome </li></ul><ul><ul><li>CD4<200 </li></ul></ul><ul><li>Opportunistic infections: </li></ul><ul><ul><li>PCP – pnuemocystis carinii </li></ul></ul><ul><ul><li>MAC – mycobacterium aviary complex </li></ul></ul><ul><ul><li>CMV – cytomegalovirus </li></ul></ul><ul><li>Other opportunists: </li></ul><ul><ul><li>HSV – herpes simplex virus </li></ul></ul><ul><ul><li>C. albicans – thrush </li></ul></ul><ul><ul><li>Toxoplasma gondii – exposure to cats </li></ul></ul><ul><ul><li>Cryptosporidium – causes diarrhea a/o obstructive jaundice </li></ul></ul>
    • 7. Disease Spectrum <ul><li>1-3 MONTHS: </li></ul><ul><li>HIV infection </li></ul><ul><li>flu like symptoms </li></ul><ul><li>1-10+ YEARS: </li></ul><ul><li>Asymptomatic </li></ul><ul><ul><li>No symptoms </li></ul></ul><ul><li>Symptomatic </li></ul><ul><ul><li>Fatigue </li></ul></ul><ul><ul><li>Diarrhea </li></ul></ul><ul><ul><li>Fever </li></ul></ul><ul><ul><li>Thrush </li></ul></ul><ul><ul><li>Skin rash </li></ul></ul><ul><ul><li>Weight loss </li></ul></ul><ul><ul><li>Swollen glands </li></ul></ul>
    • 8. The Immune System & HIV <ul><li>Function = prevent/fight disease: </li></ul><ul><ul><li>Control or eliminate viruses and other microbes that threaten the body with infection and disease. </li></ul></ul><ul><ul><li>Eliminate damaged cells that are or may be cancerous. </li></ul></ul><ul><li>The immune system is divided into two branches according to their response to disease: </li></ul><ul><ul><li>Antibody-mediated immune response  copes with disease causing microbes in the blood </li></ul></ul><ul><ul><li>Cell-mediated immune response  copes with microbes located within cells </li></ul></ul>
    • 9. Helper T Cells - CD4 Cells <ul><li>Helper cells because they coordinate & activate both B lymphocytes [antibody mediated] & cell-killing cytotoxic (CD8) lymphocytes [cell mediated] </li></ul><ul><li>Cell-mediated immune response  copes with microbes located within cells. </li></ul><ul><li>HIV infects & destroys CD4 cells </li></ul><ul><li>Loss of cells  immune system collapse & HIV disease. </li></ul><ul><li>Decline in CD4 cells is used as a marker of the progression of HIV. </li></ul>
    • 10. Cytotoxic T-Cells: CD8 Cells <ul><li>Important in initial immune response to HIV & at latent stage </li></ul><ul><li>Kills infected cells that are producing virus </li></ul><ul><li>Secrete soluble factors that suppress HIV replication-these factors block by occupying receptors necessary for the entry of certain strains of HIV into the target cell </li></ul><ul><li>New information shows two new strains of the HIV virus that target CD8 cells </li></ul>
    • 11. When to Treat Indicators <ul><li>CD4 TESTING RESULTS: </li></ul><ul><li>Vital to the immune process </li></ul><ul><li>Count=number of cells/mm3 </li></ul><ul><li>Measurement of immune function </li></ul><ul><li>Measure every 3-6 months </li></ul><ul><li>VIRAL LOAD TESTING: </li></ul><ul><li>Measures plasma HIV levels </li></ul><ul><li>Indicator of disease progression </li></ul><ul><li>Measure every 3 months </li></ul>
    • 12. AIDS <ul><li>SYMPTOMATIC: </li></ul><ul><li>any CD4/viral load value </li></ul><ul><li>treat </li></ul><ul><li>ASYMPTOMATIC: </li></ul><ul><li>CD4<500, Viral load >10,000 women, 20,000 men </li></ul><ul><li>treatment should be offered </li></ul><ul><li>CD4>500, Viral load<10,000 women, 20,000 men </li></ul><ul><li>delay treatment and monitor </li></ul>
    • 13. New Guidelines-Recommendations Defer; some treat if viral load is >55,000 / mL >350 Asymptomatic Treat; some defer especially if viral loads < 20,000 / mL 200-349 Asymptomatic Treat < 200 Asymptomatic Treat Any Symptomatic Recommendations CD4 / mcL Category
    • 14. HAART: Highly Active Antiretroviral Treatment <ul><li>Combination of multiple antiretrovirals to achieve maximum effect in viral load suppression to a goal of undetectable viral load levels </li></ul><ul><li>Base changes in Tx on: </li></ul><ul><ul><li>CD4 decline measured on 2 occasions </li></ul></ul><ul><ul><li>Virologic failure (increased HIV viral load) </li></ul></ul><ul><ul><li>Toxicity </li></ul></ul><ul><ul><li>Patient tolerance </li></ul></ul><ul><ul><li>Inability to comply with regimen </li></ul></ul>
    • 15. HAART: Highly Active Antiretroviral Treatment <ul><li>Obtain genotypic or phenotypic resistance testing while on old regimen and use information to guide selection of new regimen </li></ul><ul><li>Always change at least two of the retrovirals in the regimen </li></ul><ul><li>Avoid choosing agents with overlapping resistance patterns with those that have failed </li></ul><ul><li>Avoid agents with similar side effects as those to which a patient is intolerant </li></ul><ul><li>Simplify next regimen if possible </li></ul>
    • 16. Antiretrovirals Non-nucleoside Analogs Nucleoside Analogs SUBCLASS Delavirdine mesylate (DLV) Nevirapine (NVP) Efavirenz (EFV) Didanosine (ddI) Lamivudine (3TC) Stavudine (d4T) Zalcitabine (ddC) Zidovudine (ZDV, AZT) Abacavir (ABC) Tenofivir Disoproxil Fumarate (TDF) AZT / 3TC AZT / 3TC / ABC GENERIC Rescriptor Viramune Sustiva Videx Epivir Zerit Hivid Retrovir Ziagen Viread Combivir Trizivir Reverse Transcriptase Inhibitors TRADE CLASS
    • 17. Antiretrovirals Crixivan Viracept Norvir Invirase Agenerase Reyatz Lexiva Kaletra Indinavir sulfate (IDV) Nelfinavir mesylate (NFV) Ritonavir (RTV) Saquinavir mesylate (SQV) Amprenavir (APV) Atazanavir Fosamprenavir (f-APV) LPV / RTV Protease Inhibitors Enfuvirtide GENERIC Fuzeon, T-20 Fusion Inhibitor TRADE CLASS
    • 18. Antiretrovirals: Major Categories <ul><li>Reverse Transcriptase Inhibitors </li></ul><ul><ul><li>Act early in the life cycle of the HIV </li></ul></ul><ul><ul><li>Prevent the HIV enzyme from creating HIV proviral DNA from viral RNA  prevents new viruses from being produced </li></ul></ul><ul><ul><ul><li>Nucleoside: work by chain termination & competitive inhibition of nucleoside triphosphates </li></ul></ul></ul><ul><ul><ul><li>Non-nucleoside: Do NOT require intracellular phosphorylation for activation; directly bind to & disrupt catalytic site of reverse transcriptase  chain termination </li></ul></ul></ul>
    • 19. Antiretrovirals: Major Categories <ul><li>Protease Inhibitors </li></ul><ul><ul><li>Act late in the life cycle of the HIV </li></ul></ul><ul><ul><li>Block HIV enzyme protease  prevent creation or cleavage of HIV polyproteins necessary for production of new virions </li></ul></ul><ul><li>Fusion Inhibitor </li></ul><ul><ul><li>Attach to proteins on surface of T-cells or HIV </li></ul></ul><ul><ul><li>Prevent binding of proteins on HIV’s outer coat (GP 120, GP41) with surface receptors on T-cells (CCR5, CXCR4) </li></ul></ul><ul><ul><li>At present Enfurvirtide binds to GP 41 </li></ul></ul>
    • 20. Baseline Data Prior to Tx <ul><li>T4 (CD4) count (immune status) & plasma HIV RNA measurement (viral load – severity of infection) </li></ul><ul><ul><li>ALSO used to gauge efficacy of Tx </li></ul></ul><ul><li>CBC with diff, folate, B12, ferritin, iron, percent iron saturation </li></ul><ul><li>Hx hepatitis or hepatomegaly & alcohol use/abuse – obtain LFTs & Hep A,B,C </li></ul><ul><li>Hx pancreatitis – obtain amylase (isoamylase fractionates: salivary vs. pancreatic) </li></ul><ul><li>Triglycerides & lipase levels </li></ul><ul><li>Peripheral neuropathies – timed vibratory sensation </li></ul>
    • 21. For IDV, monitor for nephrolithisis, UA for crystalluria, increased urine pH Urinalysis If Sx of lactic acidosis associated with NNRTIs Serum Lactate Q3-4 mo, monitor for NNRTIs If elevated at baseline, monitor within 1-2 mo Lipid Profile Q 3-6 mo, more closely for pancreatitis Amylase / Lipase Frequency / Indication Lab Test Q 3-6 mo, more freq for abnl values & elevated LFTs LFTs Q 3-6 mo, Glucose monitoring Q 3-4 mo Serum Chemistries B12 deficiency m neuropathy vs. HAART Tx induced neuropathy Vitamin B12 Q 3-6 mo, more freq with low values or bone marrow toxicities CBC with DIFF Dx, before Tx, 2-8 wks after start of Tx HIV Viral Load Dx, 3-6 mo, response to Tx CD4
    • 22. Tx During Pregnancy <ul><li>Antiretroviral Pregnancy Registry (800-258-4263)  to monitor maternal-fetal outcomes of pregnant women who receive antiretrovirals </li></ul><ul><li>High risk of HIV transmission with breastfeeding – CDC advises against </li></ul>
    • 23. FDA Pregnancy Category Rating <ul><li>Animal studies  fetal risk + no controlled studies in women OR </li></ul><ul><li>No available studies in women or animals </li></ul>C <ul><li>Positive evidence of fetal risk but there may be certain situations where the benefit might outweigh the risk  life-threatening or serious diseases where other drugs are ineffective or carry a greater risk </li></ul>D <ul><li>Animal studies  no risk to fetus + no controlled studies in pregnant women OR </li></ul><ul><li>Animal studies  fetal risk , but controlled studies in pregnant women  no risk </li></ul>B DESCRIPTION CATEGORY
    • 24. Patient Education <ul><li>Compliance is essential </li></ul><ul><ul><li>Non-compliance  development of resistance </li></ul></ul><ul><li>Tx does NOT cure HIV infection </li></ul><ul><ul><li>Tx does NOT prevent transmission  MUST follow safe sex practices </li></ul></ul><ul><li>HIV(+) women: high risk of HIV transmission in breast milk </li></ul><ul><ul><li>CDC recommends HIV(+) women  NO breastfeeding </li></ul></ul><ul><li>Report: </li></ul><ul><ul><li>ALL medication usage: OTC, herbal, etc.  MANY drug interactions!!! </li></ul></ul><ul><ul><li>S/Sx’s of pancreatitis  D/C if present </li></ul></ul><ul><ul><li>S/Sx’s of peripheral neuropathy  if medication D/C’d promptly, neuropathy may be reversible  if no improvement may be r/t B12 deficiency </li></ul></ul>
    • 25. Didanosine (ddI, Videx) <ul><li>Mechanism of action </li></ul><ul><ul><li>Chain termination </li></ul></ul><ul><ul><li>Rapidly degraded in acidic pH  gastric secretions may inactivate drug  buffering agent provides proper pH for absorption </li></ul></ul><ul><ul><li>Antacids & H2 blockers increase absoprtion  may lead to toxic levels of drug </li></ul></ul><ul><li>Contraindications </li></ul><ul><ul><li>Hypersensitivity </li></ul></ul><ul><ul><li>S/Sx’s pancreatitis or serum amylase 1.5-2 x ULN </li></ul></ul><ul><ul><li>Excessive alcohol intake </li></ul></ul><ul><ul><li>Peripheral neuropathy </li></ul></ul><ul><ul><li>Pregnancy Category B </li></ul></ul>
    • 26. Didanosine (ddI, Videx) <ul><li>Warnings </li></ul><ul><ul><li>IV pentamidine & sulfonamides  pancreatitis Restart ddI in 1-2 wks d/t long ½-life of petamidine </li></ul></ul><ul><ul><li>Use with caution in pancreatitis or prior Hx of alcohol abuse </li></ul></ul><ul><ul><li>Monitor LFT closely </li></ul></ul><ul><ul><li>High magnesium levels in patients with renal impairment </li></ul></ul><ul><ul><li>PKU pts: chewable form contains NutraSweet </li></ul></ul><ul><li>Precautions </li></ul><ul><ul><li>Coadministration with food reduces absorption </li></ul></ul><ul><ul><li>May restart at a lower dose when/if peripheral neuropathy resolves </li></ul></ul><ul><ul><li>Antacids & H2 blockers may increase bioavailability </li></ul></ul><ul><ul><li>Avoid concomitant administration of zalcitabine & stavudine d/t similar toxicity profiles </li></ul></ul>
    • 27. Didanosine (ddI, Videx) <ul><li>Adverse Effects </li></ul><ul><ul><li>Pancreatitis </li></ul></ul><ul><ul><li>Peripheral neuropathy </li></ul></ul><ul><ul><li>Diarrhea </li></ul></ul><ul><ul><li>Hyperuricemia </li></ul></ul><ul><ul><li>Possible hepatic dysfunction </li></ul></ul><ul><li>Overdose </li></ul><ul><ul><li>Limited information on acute toxicity </li></ul></ul><ul><ul><li>Hemodialysis / peritoneal dialysis unknown </li></ul></ul>
    • 28. Lamivudine (3TC, Epivir) <ul><li>Mechanism of action </li></ul><ul><ul><li>Competitive inhibition </li></ul></ul><ul><ul><li>Chain termination </li></ul></ul><ul><ul><li>If used alone  resistant mutation & loss of antiretroviral effect in 8-12 wks  NOT used alone! </li></ul></ul><ul><ul><li>If used in combination with AZT (combivir)  delays emergence of mutations susceptible to either drug </li></ul></ul><ul><li>Contraindication </li></ul><ul><ul><li>Hypersensitivity </li></ul></ul><ul><ul><li>Pregnancy category C </li></ul></ul>
    • 29. Lamivudine (3TC, Epivir) <ul><li>Warnings </li></ul><ul><ul><li>Pancreatitis (rare) </li></ul></ul><ul><li>Precaution </li></ul><ul><ul><li>Reduction in dose in renal impairment </li></ul></ul><ul><ul><li>Bactrim increases blood concentration & decreases clearance of drug </li></ul></ul>
    • 30. Lamivudine (3TC, Epivir) <ul><li>Adverse effects </li></ul><ul><ul><li>COMMON: headache, nausea, malaise, fatigue, peripheral neuropathy, insomnia, nasal s/Sx’s </li></ul></ul><ul><ul><li>May cause pancreatitis in children </li></ul></ul><ul><li>Overdosage </li></ul><ul><ul><li>No known antidote </li></ul></ul><ul><ul><li>Hemodialysis / peritoneal dialysis unknown </li></ul></ul>
    • 31. Stavudine (D4T, Zerit) <ul><li>Mechanism of action </li></ul><ul><ul><li>Competitive inhibition of thymidine triphosphate </li></ul></ul><ul><ul><li>Premature chain termination </li></ul></ul><ul><li>Contraindications </li></ul><ul><ul><li>Hypersensitivity </li></ul></ul><ul><ul><li>S/Sx’s pancreatitis or serum amylase 1.5-2 x ULN </li></ul></ul><ul><ul><li>Excessive alcohol intake </li></ul></ul><ul><ul><li>Peripheral neuropathy </li></ul></ul><ul><ul><li>IN VITRO antagonistic antiviral effect with AZT  AVOID concomitant administration with AZT </li></ul></ul><ul><ul><li>Pregnancy Category C </li></ul></ul>
    • 32. Stavudine (D4T, Zerit) <ul><li>Warnings </li></ul><ul><ul><li>MAJOR TOXICITY: peripheral neuropathy </li></ul></ul><ul><ul><li>Less frequent (1%) BUT fatal pancreatitis </li></ul></ul><ul><ul><li>IV pentamidine & sulfonamides  pancreatitis Restart D4T in 1-2 wks d/t long ½-life of petamidine </li></ul></ul><ul><ul><li>Carefully monitor if Hx of alcohol abuse </li></ul></ul><ul><li>Precautions </li></ul><ul><ul><li>Monitor for peripheral neuropathy & elevated liver transaminases  if toxicity  HOLD dose </li></ul></ul><ul><ul><li>If peripheral neuropathy & hepatic dysfunction resolve may restart D4T at lowered dose </li></ul></ul><ul><ul><li>Use with caution in combination with other reverse transcriptase inhibitors with similar toxicity profiles </li></ul></ul><ul><ul><li>Reduced dosage or contraindicated in renal impairment </li></ul></ul>
    • 33. Stavudine (D4T, Zerit) <ul><li>Adverse effects </li></ul><ul><ul><li>MOST COMMON: peripheral neuropathy & asymptomatic elevation of hepatic transaminases </li></ul></ul><ul><li>Overdosage </li></ul><ul><ul><li>No acute toxicity noted </li></ul></ul><ul><ul><li>Complications of chronic overdosage: hepatic toxicity & peripheral neuropathy </li></ul></ul><ul><ul><li>Hemodialysis / peritoneal dialysis unknown </li></ul></ul>
    • 34. Zalcitabine (ddC, Hivid) <ul><li>Mechanism of action </li></ul><ul><ul><li>Competitive inhibition of natural substrate in formation of reverse transcriptase  premature termination of growing DNA chain </li></ul></ul><ul><li>Contraindications </li></ul><ul><ul><li>Hypersensitivity </li></ul></ul><ul><ul><li>S/Sx’s pancreatitis or serum amylase 1.5-2 x ULN </li></ul></ul><ul><ul><li>Excessive alcohol intake </li></ul></ul><ul><ul><li>Peripheral neuropathy </li></ul></ul><ul><ul><li>Pregnancy category C </li></ul></ul>
    • 35. Zalcitabine (ddC, Hivid) <ul><li>Warnings </li></ul><ul><ul><li>IV pentamidine & sulfonamides  pancreatitis Restart D4T in 1-2 wks d/t long ½-life of petamidine </li></ul></ul><ul><ul><li>Can cause severe peripheral neuropathy  best to avoid combinations with other antiretrovirals with similar toxicity profiles (e.g., ddI) </li></ul></ul><ul><ul><li>RARE BUT FATAL: lactic acidosis w/o hypoxemia & severe hepatomegaly w/steatosis; hepatic filaure & death in pts w/underlying hepatitis B </li></ul></ul>
    • 36. Zalcitabine (ddC, Hivid) <ul><li>Precautions </li></ul><ul><ul><li>Hx pancreatitis & peripheral neuropathy </li></ul></ul><ul><ul><li>Obese women with known risk factors for liver disease </li></ul></ul><ul><ul><li>May cause myelosuppression </li></ul></ul><ul><ul><li>Concomitant use with cimetidine increases serum concentration  increased toxicity </li></ul></ul><ul><ul><li>Mg & Al antacids decreases absorption </li></ul></ul><ul><ul><li>Metoclopramide reduces bioavailability </li></ul></ul><ul><ul><li>Probenecid decreases elimination & may lead to toxic effects </li></ul></ul><ul><ul><li>Nephrotoxic drug (e.g., ampho B) may decrease renal clearance </li></ul></ul><ul><ul><li>Renal impairment  greater risk for toxicity d/t decreased clearance </li></ul></ul><ul><ul><li>Food decreases rate & extent of oral absorption </li></ul></ul>
    • 37. Zalcitabine (ddC, Hivid) <ul><li>Adverse effects </li></ul><ul><ul><li>MOST COMMON: peripheral neuropathy, oral ulcers, aphthous stomatitis, esophageal ulceration, abnormal hepatic function, neutropenia, anemia, thrombocytopenia, fever, pruritic maculopapular rash </li></ul></ul><ul><ul><li>RARE BUT HIGH MORBIDITY/MORTALITY: pancreatitis also cardiomyopathy </li></ul></ul><ul><li>Overdosage </li></ul><ul><ul><li>No known antidote – Tx w/gastric lavage </li></ul></ul><ul><ul><li>Hemodialysis / peritoneal dialysis unknown </li></ul></ul>
    • 38. Zidovudine (ZDV, AZT, Retrovir) <ul><li>Mechanism of action </li></ul><ul><ul><li>Competitive inhibition of thymidine triphosphate & prevents cross linkages </li></ul></ul><ul><ul><li>Premature chain termination </li></ul></ul><ul><ul><li>Penetrates CSF  effective in reducing AIDS dementia complex in adults & children </li></ul></ul><ul><li>Contraindications </li></ul><ul><ul><li>Life-threatening allergic reactions </li></ul></ul><ul><ul><li>Ribavirin antagonizes antiviral activity  do NOT give concomitantly </li></ul></ul><ul><ul><li>Pregnancy category C </li></ul></ul>
    • 39. Zidovudine (ZDV, AZT, Retrovir) <ul><li>Warnings </li></ul><ul><ul><li>Hypersensitivity: rash & anaphylaxis </li></ul></ul><ul><ul><li>Metabolized by liver excreted in kidney  dosage reduction in renal impairment </li></ul></ul><ul><ul><li>Impaired liver function  increased toxicity risk </li></ul></ul><ul><ul><li>RARE BUT FATAL: lactic acidosis w/o hypoxemia & severe hepatomegaly w/steatosis (esp. in obese women) </li></ul></ul>
    • 40. Zidovudine (ZDV, AZT, Retrovir) <ul><li>Precautions </li></ul><ul><ul><li>Bone marrow suppression (combined effect w/ganciclovir & interferon alpha or B12 & other deficiencies) </li></ul></ul><ul><ul><li>Elevated MCV (megaloblastic change MUST r/o B12 or folate deficiency) </li></ul></ul><ul><ul><li>Probenecid increases drug levels  flulike Sx’s </li></ul></ul><ul><ul><li>Trimethoprim increases serum levels </li></ul></ul><ul><ul><li>Alters dilantin levels </li></ul></ul><ul><ul><li>In combo with acyclovir  drowsiness & lethargy </li></ul></ul><ul><ul><li>Methodone increases serum concentration & toxicity risk </li></ul></ul>
    • 41. Zidovudine (ZDV, AZT, Retrovir) <ul><li>Adverse effects </li></ul><ul><ul><li>MOST COMMON: myelosuppression (macrocytic anemia or granulocytopenia), myalgias, malaise, nausea & headaches (diminish over time), excessive eyelash growth, hyperpigmentation of nails (bluish) </li></ul></ul><ul><ul><li>LONG-TERM: myalgias & myositis (d/t mitochondrial toxicity)  D/C or dose reduction If inflammatory, myalgias may not improve on D/C </li></ul></ul><ul><li>Overdosage </li></ul><ul><ul><li>No fatal overdoses; one report of grand mal seizure </li></ul></ul><ul><ul><li>Hemodialysis & peritoneal dialysis  negligible effect on removal BUT elimination of primary metabolite enhanced </li></ul></ul>
    • 42. Delavirdine Mesylate (DLV, Rescriptor) <ul><li>Mechanism of action </li></ul><ul><ul><li>Directly binds to reverse transcriptase & blocks process of viral RNA transcription into proviral DNA </li></ul></ul><ul><li>Contraindications </li></ul><ul><ul><li>Hypersensitivity </li></ul></ul><ul><ul><li>Pregnancy category C </li></ul></ul>
    • 43. Delavirdine Mesylate (DLV, Rescriptor) <ul><li>Warnings </li></ul><ul><ul><li>Resistant virus emerges if given as monotherapy  always given in combination w/other retroviral </li></ul></ul><ul><ul><li>Inhibits P450 & can result in serious life threatening events </li></ul></ul><ul><li>Precautions </li></ul><ul><ul><li>Increases levels of certain drugs  watch for drug interactions (including coumadin & anticonvulsants) </li></ul></ul><ul><ul><li>Antacids decrease absorption; H2 blockers may do same </li></ul></ul>
    • 44. Delavirdine Mesylate (DLV, Rescriptor) <ul><li>Adverse effects </li></ul><ul><ul><li>MOST COMMON: skin rash w/pruritis, headache, nausea, diarrhea, fatigue </li></ul></ul><ul><ul><li>Reversible elevations in liver enzymes & bilirubin </li></ul></ul><ul><ul><li>RARE: neutropenia & anemia </li></ul></ul><ul><li>Overdosage </li></ul><ul><ul><li>No specific antidote  gastric lavage or emesis </li></ul></ul>
    • 45. Nevirapine (NVP, Viramune) <ul><li>Mechanism of action </li></ul><ul><ul><li>Directly binds to reverse transcriptase & blocks process of viral RNA transcription into proviral DNA </li></ul></ul><ul><ul><li>Autoinduction: induces own metabolism (clearance increases two-fold in first wks of use  requires increased dose at end of wk 2) </li></ul></ul><ul><li>Contraindications </li></ul><ul><ul><li>Hypersensitivity </li></ul></ul><ul><ul><li>Pregnancy category C </li></ul></ul>
    • 46. Nevirapine (NVP, Viramune) <ul><li>Warnings </li></ul><ul><ul><li>Resistant virus emerges if given as monotherapy  always given in combination w/other retroviral </li></ul></ul><ul><li>Precautions </li></ul><ul><ul><li>No dosage increases if rash in first 14 days until rash resolves </li></ul></ul><ul><ul><li>Caution in renal or hepatic dysfunction </li></ul></ul><ul><ul><li>Hepatitis has been reported </li></ul></ul><ul><ul><li>Metabolized by P450 CYP3A  interactions with drugs that share same enzyme system </li></ul></ul>
    • 47. Nevirapine (NVP, Viramune) <ul><li>Adverse effects </li></ul><ul><ul><li>MOST SIGNIFICANT (also common): Severe rash including SJS  can be life threatening </li></ul></ul><ul><ul><li>If severe rash or rash in combination w/ fever, blistering, oral lesion, conjunctivitis, swelling, myalgias or arthralgias  D/C immediately (usu. occurs in first 4 wks but may be as late as 8 wks) </li></ul></ul><ul><ul><li>MOST COMMON: fever, nausea, headache, abnormal LFTs </li></ul></ul><ul><li>Overdosage </li></ul><ul><ul><li>No known antidote </li></ul></ul>
    • 48. Indinavir Sulfate (Crixivan) <ul><li>Mechanism of action </li></ul><ul><ul><li>Binds to active site on protease enzyme  inhibits activity of enzyme  blocks cleavage/division of viral proteins needed to make infectious HIV virions </li></ul></ul><ul><li>Contraindications </li></ul><ul><ul><li>Hypersensitivity </li></ul></ul><ul><ul><li>Metabolized through P450 CYP3A4 competes with & inhibits drugs which share same enzyme system  may lead to toxic levels of other drugs </li></ul></ul><ul><ul><li>Rifampin is a potent inducer of CYP3A4  decreases serum concentration of idinavir </li></ul></ul><ul><ul><li>Pregnancy category C </li></ul></ul>
    • 49. Indinavir Sulfate (Crixivan) <ul><li>Warnings </li></ul><ul><ul><li>May cause nephrolithiasis d/t crystallization of drug  adequate hydration required </li></ul></ul><ul><ul><li>May require holding dose during acute episode </li></ul></ul><ul><li>Precautions </li></ul><ul><ul><li>Sensitive to moisture  keep in original bottle w/desiccant </li></ul></ul><ul><ul><li>Separate didanosine & indinavir by 2 hrs Normal gastric pH needed for absorption of indinavir BUT didanosine is degraded by acid & requires buffer </li></ul></ul>
    • 50. Indinavir Sulfate (Crixivan) <ul><li>Adverse effects </li></ul><ul><ul><li>MOST SIGNIFICANT: nephrolithiasis </li></ul></ul><ul><ul><li>COMMON: abdominal pain, nausea, vomiting, diarrhea, back pain, headahce, insomnia, altered taste </li></ul></ul><ul><ul><li>Also: hyperbilirubinemia & increases in serum transaminases </li></ul></ul><ul><ul><li>Lactose intolerant may have greater difficulty w/diarrhea as primary inactive ingredient = lactose </li></ul></ul><ul><li>Overdosage </li></ul><ul><ul><li>No data available on overdosage </li></ul></ul><ul><ul><li>Hemodialysis / peritoneal dialysis unknown </li></ul></ul>
    • 51. Nelfinavir Mesylate (Viracept) <ul><li>Mechanism of action </li></ul><ul><ul><li>Binds to active site on protease enzyme  inhibits activity of enzyme  blocks cleavage/division of viral proteins needed to make infectious HIV virions </li></ul></ul><ul><ul><li>Plasma concentrations 2-3x higher with food </li></ul></ul><ul><li>Contraindications </li></ul><ul><ul><li>Hypersensitivity </li></ul></ul><ul><ul><li>Metabolized through P450 CYP3A4 competes with & inhibits drugs which share same enzyme system  may lead to toxic levels of other drugs </li></ul></ul><ul><ul><li>Rifampin is a potent inducer of CYP3A4  decreases serum concentration of nelfinavir </li></ul></ul><ul><ul><li>Pregnancy category B </li></ul></ul>
    • 52. Nelfinavir Mesylate (Viracept) <ul><li>Precautions </li></ul><ul><ul><li>Metabolized through P450 CYP3A4 competes with & inhibits drugs which share same enzyme system  may lead to toxic levels of other drugs </li></ul></ul><ul><ul><li>Give with caution in hepatic impairment </li></ul></ul><ul><ul><li>Plasma concentrations of OCPs may be decreased </li></ul></ul><ul><ul><li>Reduce rifabutin dose in half if given concomitantly (decreases plasma concentration of nelfinavir by 37-207%) </li></ul></ul>
    • 53. Nelfinavir Mesylate (Viracept) <ul><li>Adverse effects </li></ul><ul><ul><li>MOST COMMON: diarrhea nausea & vomiting when given with AZT </li></ul></ul><ul><li>Overdosage </li></ul><ul><ul><li>No specific antidote </li></ul></ul><ul><ul><li>Emesis or gastric lavage </li></ul></ul><ul><ul><li>Also: activated charcoal </li></ul></ul>
    • 54. Ritonavir (Norvir) <ul><li>Mechanism of action </li></ul><ul><ul><li>Binds to active site on protease enzyme  inhibits activity of enzyme  blocks cleavage/division of viral proteins needed to make infectious HIV virions </li></ul></ul><ul><ul><li>Absorption improved by 15% when taken with food </li></ul></ul><ul><li>Contraindications </li></ul><ul><ul><li>Hypersensitivity </li></ul></ul><ul><ul><li>Large increases in plasma concentrations of oxidatively metabolized drugs (esp. hypnotic & sedative drugs  dangerous toxicities including arrhthmias & respiratory depression  contraindicated w/ritonavir) </li></ul></ul><ul><ul><li>Pregnancy category B </li></ul></ul>
    • 55. Ritonavir (Norvir) <ul><li>Warnings </li></ul><ul><ul><li>Large number of potential drug interactions </li></ul></ul><ul><ul><li>Caution in impaired liver function </li></ul></ul><ul><ul><li>Contains alcohol in formulation  coadministration of disulfuram or metronidazole  antabuse-type reaction </li></ul></ul><ul><li>Precautions </li></ul><ul><ul><li>Tobacco decreases plasma concentration </li></ul></ul><ul><ul><li>Many drug interactions including OCPs </li></ul></ul>
    • 56. Ritonavir (Norvir) <ul><li>Adverse effects </li></ul><ul><ul><li>MOST COMMON: generalized weakness, nausea, vomiting, diarrhea, anorexia, abdominal pain, change in taste, numbness & tingling around mouth, paresthesias </li></ul></ul><ul><ul><li>Fewer GI side effects if taken w/high fat meal </li></ul></ul><ul><ul><li>GI effects sibside over time (4-5 wks) </li></ul></ul><ul><ul><li>LABS: elevations in hepatic transaminases, bilirubin, triglycerides, creatinine phosphokinase, & uric acid </li></ul></ul><ul><li>Overdosage </li></ul><ul><ul><li>Limited information & no specific antidote </li></ul></ul><ul><ul><li>Emesis or gastric lavage </li></ul></ul><ul><ul><li>Dialysis NOT helpful as drug is highly protein-bound& extensively metabolized by liver </li></ul></ul>
    • 57. Saquinavir Mesylate (Invirase) <ul><li>Mechanism of action </li></ul><ul><ul><li>Binds to active site on protease enzyme  inhibits activity of enzyme  blocks cleavage/division of viral proteins needed to make infectious HIV virions </li></ul></ul><ul><li>Contraindications </li></ul><ul><ul><li>Hypersensitivity </li></ul></ul><ul><ul><li>Rifampin decreases serum concentration 80% </li></ul></ul><ul><ul><li>Metabolized through P450 CYP3A4 competes with & inhibits drugs which share same enzyme system  may lead to toxic levels of other drugs </li></ul></ul><ul><ul><li>Pregnancy category B </li></ul></ul>
    • 58. Saquinavir Mesylate (Invirase) <ul><li>Warnings </li></ul><ul><ul><li>Metabolized through P450 CYP3A4 competes with & inhibits drugs which share same enzyme system  may lead to toxic levels of other drugs </li></ul></ul><ul><ul><li>Many drug interactions </li></ul></ul><ul><li>Precautions </li></ul><ul><ul><li>Caution in hepatic insufficiency </li></ul></ul>
    • 59. Saquinavir Mesylate (Invirase) <ul><li>Adverse effects </li></ul><ul><ul><li>MOST COMMON: diarrhea, abdominal discomfort, nausea </li></ul></ul><ul><ul><li>Lactose intolerant may have greater difficulty w/diarrhea as primary inactive ingredient = lactose </li></ul></ul><ul><li>Overdosage </li></ul><ul><ul><li>Information limited </li></ul></ul><ul><ul><li>Emesis </li></ul></ul>
    • 60. Enfuvirtide (Fuzeon, T-20) <ul><li>Contraindications </li></ul><ul><ul><li>Hypersensitivity </li></ul></ul><ul><li>Warnings </li></ul><ul><ul><li>Local injection site reaction: pain, induration, erythema, nodules, cysts, pruritis, ecchymosis </li></ul></ul><ul><ul><li>Increased rate of bacterial pneumonia – monitor for s/s of pneumonia </li></ul></ul><ul><ul><li>Hypersensitivity reaction may occur on rechallenge – D/C drug on development of Sx’s suggestive of systemic hypersensitivity </li></ul></ul>
    • 61. Retrovirus: DNA Transcription
    • 62. Retrovirus: Viral RNA Transcription
    • 63. Retrovirus Production
    • 64. Viral Replication
    • 65. Steps of Viral Replication <ul><li>HIV binds to CD4 cell.RNA, proteins & enzymes released. </li></ul><ul><li>HIV reverse transcriptase converts viral RNA into DNA. </li></ul><ul><li>HIV DNA moves to nucleus & spliced into host’s DNA. </li></ul><ul><li>HIV RNA moves out of the nucleus into cytoplasm & makes long chains of viral proteins & enzymes. </li></ul><ul><li>Immature viral particle forms containing cellular & HIV proteins. Chains cut into smaller pieces by protease. </li></ul><ul><li>Infectious viral particle ready to be released containing HIV RNA, viral proteins & enzymes. </li></ul>
    • 66. HIV Testing <ul><li>p24 Antigen </li></ul><ul><ul><li>Used to detect HIV antigen in children younger than 18 months </li></ul></ul><ul><ul><li>Test can be useful at any age </li></ul></ul><ul><ul><li>Only a positive result is significant </li></ul></ul><ul><ul><li>Two or more positive results are diagnostic for HIV infection </li></ul></ul><ul><li>CD4+ </li></ul><ul><ul><li>Used to assess immune status, risk for disease progression, and need for PCP prophylaxis </li></ul></ul>

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