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Pharmacology

Pharmacology. Unit 7 HIV Care and ART: A Course for Physicians. Learning Objectives. Describe the mechanism of action of antiretroviral (ARV) drugs List the common side effects of ARVs List the standard ARV doses

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Pharmacology

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  1. Pharmacology Unit 7 HIV Care and ART: A Course for Physicians

  2. Learning Objectives • Describe the mechanism of action of antiretroviral (ARV) drugs • List the common side effects of ARVs • List the standard ARV doses • Identify the ARVs that require dose adjustment for patients with renal or hepatic disease • List the ARVs that have food requirements

  3. Learning Objectives (2) • Describe the mechanisms of drug interactions relevant to ARVs • Identify commonly used drugs that may have important interactions with ARVs • Describe the principles and mechanisms of drug resistance

  4. Antiretroviral Drugs

  5. Ethiopian ART Guideline

  6. 2003 vs. 2005 WHO Guidelines

  7. Classes of Antiretrovirals • NRTIs • Nucleoside reverse transcriptase inhibitors • Nucleotide reverse transcriptase inhibitors (NtRTI) • NNRTIs – non-nucleoside reverse transcriptase inhibitors • PIs – protease inhibitors • Fusion Inhibitors

  8. ARVs and the HIV Lifecycle

  9. Nucleoside Reverse Transcriptase Inhibitors (NRTIs) RNA DNA Nucleus Host Cell

  10. Types of NRTIs • Zidovudine (AZT) • Stavudine (d4T) • Lamivudine (3TC) • Didanosine (ddI) • Abacavir (ABC) • Zalcitabine (ddC) • Emtricitabine (FTC) • Tenofovir (TDF)-Nucleotide RTI

  11. Zidovudine (AZT, ZDV) • Dosing: 300mg BID • Food Interactions • None – can take with or without food • Food decreases AZT-related nausea

  12. Nausea Bone Marrow Suppression Anemia Neutropenia Headache Myalgia Myopathy Insomnia Pigmentation of nail beds Lactic acidosis, fatty liver ZDV: Toxicity

  13. ZDV: Bone Marrow Suppression • Correlates with drug dose & duration, marrow reserve, and stage of disease • Anemia occurs after 4-6 weeks • Neutropenia occurs after 12-24 weeks • Marrow histology shows normal or reduced RBC precursors • Management • Stop AZT if Hgb <8 gm/dl • Hgb typically recovers in 1 to 2 weeks

  14. ZDV-Related Fingernail Discoloration • Nail Hyperpigmentation • Can be seen on hands and feet after 2-6 weeks • Usually dark bluish-black vertical-line discoloration • More common among African population • This is NOT an indication to stop ZDV

  15. Lamivudine (3TC) • Dosing: 150mg BID or 300mg QD • Food Interactions: none • Toxicity: very rare • Component of all first-line regimens • Also active against Hepatitis B • Main disadvantage: rapid development of resistance

  16. Emtricitabine (FTC) • Dosing: 1 x 200mg capsule QD • Food Interactions: no food interactions • Toxicity • Mild abdominal discomfort • Occasional nausea • Emtricitabine is the fluorinated version of lamivudine

  17. Hepatitis B Co-infection • Drugs active against both HBV & HIV: 3TC, FTC, TDF • HBV develops rapid resistance to 3TC and FTC • TDF + (3TC or FTC) is the optimal NRTI backbone • Differential diagnosis of exacerbation of hepatic disease in these patients: • Development of 3TC or FTC resistance • “HBV flair” secondary to stopping 3TC or FTC • ART related hepatoxocity (AZT, d4T, ddI, EFV, NVP, All PIs) • Immune reconstitution syndrome

  18. Lamivudine + Zidovudine • Dosing: 1 tablet (150 / 300mg) BID • Food Interactions • None – with or without food is ok • Food decreases ZDV-related nausea

  19. Stavudine (d4T) • Dosing • 40 mg BID for weight > 60 kg • 30 mg BID for weight < 60 kg • Food Interactions: None • Toxicity (use lower dose to reduce risk of S/E development for patients < 60kg) • Peripheral Neuropathy (5-15%, pain, tingling, and numbness in extremities) • Lactic acidosis, fatty liver • Lipoatrophy • Pancreatitis • Hypertriglyceridemia

  20. d4T: Dose-related Side Effects • Peripheral Neuropathy: • Onset usually after 2-6 months of therapy. • If develops: discontinue d4T at onset (or reduce dose to 20mg Q12H if weight > 60kg, or 15mg Q12H if < 60kg) • Lipoatrophy: • loss of fat tissue on arms, legs, and face • Pancreatitis: • If develops, discontinue therapy. • When symptoms resolve, do not re-challenge with stavudine

  21. Facial Lipoatrophy © ITECH, 2006

  22. Abacavir (ABC) • Dosing: 1 x 300mg tablet BID • Food Interactions: no food interactions • Generally well tolerated • Toxicity • Hypersensitivity reaction • Occurs within first 6 weeks of therapy

  23. Hypersensitivity to Abacavir • Observed in approximately 5% of all patients receiving abacavir • Multi-organ system involvement • Most common signs and symptoms: • Fever (>80%) • Rash (maculopapular or urticarial) (70%) • Fatigue (>70%) • Flu-like symptoms (50%) • GI (nausea, vomiting, diarrhea, abdominal pain) (50%)

  24. Hypersensitivity to Abacavir (2) • Counsel and prepare patient for hypersensitivity symptoms and to contact provider/pharmacist immediately • Especially during first month of therapy • Provider/pharmacist determines cause of symptoms: abacavir or not • Hypersensitivity may be fatal (19 deaths) • NEVER rechallenge • Genetic predisposition • Similar to life-threatening reaction to NVP

  25. Abacavir Re-challenge • 20% risk of anaphylactic-like reaction upon re-challenge • Death can occur with hours of restarting • Symptoms may include include: • hypotension • bronchoconstriction • renal failure • Laboratory changes may include • Increased CPK • Elevated liver function tests • Reduced lymphocyte count Abacavir should never be re-challenged!

  26. Tenofovir Disoproxil Fumarate (TDF) • Dosing: 1 x 300mg tablet QD • Food Interactions: None • Very well tolerated, side effects are minimal • Toxicity • Renal insufficiency (rare) • Must dose adjust with renal failure • Also has activity against Hepatitis B • Dosed 300mg QD • Active against Lamivudine resistant HBV strains • HBV resistance 1% at 1 year • If TDF is stopped, may have HBV hepatitis flare

  27. Didanosine (ddI) • Requires a basic environment • Food Interactions: take on empty stomach • Dosing (one of the following) • 1 x 400mg enteric coated capsule QD (if <60kg: 250mg QD) • 2 x 100mg buffered tab BID or 4 x 100mg QD (if <60kg: 125 mg BID or 250mg QD) • NOTE: If use buffered tablets, 2 or more tablets must be used at each dose to provide adequate buffer • 250mg of reconstituted buffered powder BID (if <60kg: 167mg BID) • Mix pediatric powder with liquid antacid

  28. Didanosine (ddl) (2) • If taken with TDF must reduce ddI dose: • > 60 kg < 60 kg • 250 mg/d 200 mg/d • Without dose adjustment – blunted CD4 response • Toxicity • Peripheral Neuropathy • GI intolerance • Pancreatitis (7%2%) • Lactic acidosis, fatty liver

  29. NRTI Class Side Effects • As with all antiretrovirals, side effects are worst during the first 1 to 2 weeks of therapy. • Counsel patients • Potential for side effects • How to handle side effects • Don’t give up

  30. NRTI Class Side Effects (2) • Peripheral Neuropathy: ddl + d4T • With continued treatment may be irreversible • Lactic Acidosis, fatty liver: d4T > ddl > AZT • Lipoatrophy: d4T > AZT • Pancreatitis: ddl > d4T • Marrow Suppression: AZT

  31. NRTI Mitochondrial Toxicity • Inhibition of mitochondrial DNA polymerase- •  oxidative metabolism,  ATP generation • Implicated in lactic acidosis with hepatic steatosis • Other possible manifestations: • Neuropathy (d4T, ddI) • Lipoatrophy (d4T) • Pancreatitis (ddI) • Myopathy (AZT) • Cardiomyopathy (AZT)

  32. Hyperlactatemia/Lactic Acidosis • Rare but potentially fatal syndrome (1/1000 pt/yrs) • Linked to prolonged use of NRTIs, especially ddI and d4T • Acute or subacute onset • Symptoms: nausea, vomiting, weight loss, fatigue • Lab: increased anion gap (or lactate level) • Ultrasound: fatty liver • Management: discontinue NRTI – may take months to reverse. No specific treatment

  33. Neucloside Pairings

  34. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

  35. Non-Nucleoside Reverse Transcriptase Inhibitors • NNRTIs • Nevirapine (NVP) • Efavirenz (EFV)

  36. Nevirapine (NVP) • Dosing: 200 mg QD x 2 weeks, then 200 mg BID • Food Interactions: None • Toxicity • Rash (17%) • Nausea & vomiting • Hepatitis (8-18%) • Risk is greatest in first 6 weeks of therapy • Could be benign or fatal • Black Box warning by FDA (USA): • Do not use NVP in women w/ starting CD4>250 • Do not use NVP in men w/ starting CD4> 400

  37. Hepatotoxicity: NVP & PIs • NVP: • Hepatic necrosis 1st 6-16 weeks after starting Rx • Those at higher risk for hepatitis include: • Patients with a history of alcohol abuse, coinfection with hepatitis B or C and in patients who are older or are women. • Persons with higher CD4 cell counts or elevated LFTs at baseline • PI & NNRTIs: All cause ↑ ALT/AST in 10-15%

  38. Hepatotoxicity: NVP & PI (2)

  39. NVP: Hepatotoxicity “Symptomatic Hepatitis”

  40. NVP for PMTCT • Issue is RESISTANCE and EFFICACY • No SAFETY concerns

  41. Nevirapine-Induced Rash Courtesy of HIV Web Study, www.hivwebstudy.org

  42. Nevirapine-Induced Rash (2) • To reduce the risk • The dose should be escalated over the first 2 weeks • Starting at 200mg QD for 2 weeks and then increasing to 200mg BID • This dosing makes sense because nevirapine autoinduces hepatic cytochrome P450 enzymes (CYP3A4) • Which reduces its own half-life over 2 to 4 weeks from 45 to 25 hours.

  43. Efavirenz (EFV) • Dosing: 3 x 200mg capsules or 600mg tab QHS • Food Interactions • Take on an empty stomach or with low-fat meal • High-fat meals increase absorption by 50%  increases side effects • Consistent results: persistent activity after >5 years • Never surpassed in clinical trial

  44. Efavirenz Toxicity • CNS Changes (52%) • Rash (15-27%) usually does not require discontinuation • Hepatotoxicity (2-8% experience increase in LFTs > 5 ULN) • Contraindicated during pregnancy • Teratogenic—Class D

  45. Efavirenz CNS Toxicity • Symptoms: confusion, Insomnia, nightmares, poor concentration, mood change, dizziness, dysequilibrium, depression, psychosis, “disconnected” • Onset: first dose • Course: usually resolves in 2-3 weeks • Cause: Unknown • Management: warn patient

  46. Which Third Drug to Use?

  47. EFV vs. NVP

  48. NNRTI Class Effects • Side effects • Rash • Hepatotoxicity • Cross resistance: • A single mutation, the K103N, causes high-level resistance to all 3 drugs in this class: EFV, NVP, and DLV • Latent pool forever • Importance of adherence

  49. NNRTI Rash • Often diffuse, slightly raised, itchy • Vary in redness and distribution • Can be severe - Steven’s Johnson Syndrome Courtesy of the Public Health Image Library/CDC/ J. Pledger, BSS/VD

  50. Protease Inhibitors (PIs) DNA Host Cell

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