Anti retroviral agents (ar vs) for midwives

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Anti retroviral agents (ar vs) for midwives

  1. 1. Anti-Retroviral Agents (ARVs) BY; SEYOUM GIZACHEW (B.Pharm., MSc)
  2. 2. Anti-Retroviral Agents (ARVs) HIV-1 Virology 2
  3. 3. The HIV Epidemic Unfolds • Sudden outbreak in USA of opportunistic infections and cancers in homosexual men in 1981. – Pneumocystis carinii pneumonia (PCP), Kaposi’s sarcoma, and non-Hodgkins lymphoma • HIV isolated in 1984 - Luc Montanier (Pasteur Institute, Paris) and Robert Gallo (NIH, Bethesda, USA) • HIV diagnostic tests developed in 1985. • First antiretroviral drug, zidovudine, developed in 1986 • Exploding pandemic. – Has infected more than 50 million people around the world – Has killed over 22 million people. 3
  4. 4. Classification of HIV • Retrovirus: single stranded RNA transcribed to double stranded DNA by reverse transcriptase • Integrates into host genome • Can lie dormant within a cell for many years, especially in resting (memory) CD4+ T4 lymphocytes • HIV type (distinguished genetically) – HIV-1 -> worldwide pandemic (~ 40 M people) – HIV-2 -> isolated in West Africa; causes AIDS much more slowly than HIV-1 but otherwise clinically similar. 4
  5. 5. 5
  6. 6. 6
  7. 7. How HIV Enters Cells • There are three crucial steps for entry of HIV into the CD4 T cell: 1.Binding of HIV via the gp120 envelope protein to the CD4 receptor (attachment), 2.Binding to coreceptors via conformational changes to gp120, and finally 3.Fusion of virus and cell • In addition to the CD4 receptor, HIV requires coreceptors for entry into the target cell. • The two most important ones are CXCR4 and CCR5. • HIV variants mainly using CCR5 are referred to as R5 viruses; those using CXCR4 are referred to as X4 viruses. 7
  8. 8. How HIV Enters Cells cont… • When the virus enters the blood, it binds a protein on its surface (gp120) to a CD4 receptor and co-receptors (CXCR4 or CCR5) on the CD4 cell. • Then gp120 shifts to expose gp41. • Once exposed, gp41 pierces the CD4 cell and pulls it in close enough to allow viral-cell fusion. • Binding of virus to cell surface results in fusion of viral envelope with cell membrane. • Viral core is released into cell cytoplasm. 8
  9. 9. HIV and Cellular Receptors 9
  10. 10. Viral-host Dynamics • About 1010 (10 billion) virions are produced daily • Average life-span of an HIV virion in plasma is ~6 hours • Average life-span of an HIV-infected CD4 lymphocytes is ~1.6 days • HIV can lie dormant within a cell for many years, especially in resting (memory) CD4 cells, unlike other retroviruses. • The extremely high rates of viral replication results in every possible point mutation in the viral genome arising daily. • In any given patient, the virus usually varies by 1-6% in the env gene, for example. 10
  11. 11. 11
  12. 12. HIV Life Cycle and Sites for Therapeutic Intervention 12
  13. 13. Classes of Antiretrovirals • Fusion inhibitors – Prevents fusion of the virus into a CD4 cell by preventing conformational change needed to allow virus to enter a CD4 cell • Nucleoside reverse transcriptase inhibitors (NRTIs) or nukes (zidovudine, lamivudine) – Mimic naturally occurring nucleosides – Blocks viral DNA construction as they deceive reverse transcriptase. • Non- nucleoside reverse transcriptase inhibitors (NNRTIs) or non-nukes (Nevirapine, Efavirenz) – Bind to the reverse transcriptase enzyme • Protease inhibitors (PIs) (Indinavir, lopinavir) – Prevents cleavage of precursor protein chains. 13
  14. 14. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI’s) • • • • • • • • Lamivudine (3TC) Stavudine (d4T) Zidovudine (ZDV, AZT) Didanosine (ddI) Tenofovir (TDF) Abacavir(ABC) Emtricitabine(FTC) Zalcitabine(DDC) 14
  15. 15. NRTI Mechanism of Action • NRTIs must first undergo intracellular phosphorylation to be active. • NRTIs inhibit the viral reverse transcriptase enzyme – Enzyme responsible for transcribing viral RNA into double stranded DNA • NRTIs mimic other nucleosides and are incorporated into the DNA strand • They prevent the addition of the natural nucleosides into the DNA strand • This halts the production of new virions 15
  16. 16. NRTI Class Side Effects • • • • • • Nausea Headache Peripheral Neuropathy (DDC > d4T/ddI) Lipoatrophy Pancreatitis (ddI > d4T) Lactic Acidosis – d4T > ddI > ZDV – Rare with ABC, TDF, 3TC and FTC 16
  17. 17. Zidovudine (ZDV) • • • • • • • • It is a deoxythymidine analog. Phosphorylated by cellular thymidine kinase. incorporated into DNA chain and terminates synthesis. well absorbed from the gut and distributed to most body tissues and fluids, including the cerebrospinal fluid The most common adverse effect is myelosuppression, resulting in macrocytic anemia. Food decreases ZDV-related nausea Pregnancy: category C Advocated for pregnant women beyond first trimester to prevent vertical transmission. 17
  18. 18. Zidovudine (ZDV) cont… • Elimination: Metabolized by liver to 5’-glucuronyl zidovudine, which is renally excreted. – Reduce dose with renal or hepatic compromise: • Drug Interactions: ZDV and D4T compete for activation by thymidine kinase. • Combinations containing AZT plus d4T, is therefore pointless, since both drugs would compete for the same bases. • The combination of these drugs is antagonistic in vitro and in vivo: do not use together. 18
  19. 19. Zidovudine (ZDV) cont… • Toxicity – Nausea – Bone Marrow Suppression • Anemia (fatigue) • Granulocytopenia (low platelet count) • Neutropenia (low white blood cell [neutrophils] count) – Headaches – Myalgia – Myopathy – Insomnia – Pigmentation of nail beds – Lactic acidosis 19
  20. 20. Lamivudine (3TC) • A synthetic nucleoside (cytidine) analogue reverse transcriptase inhibitor • Active against HIV-1, HIV-2, and hepatitis B virus. • Phosphorylated 3 times by thymidine kinase to the active metabolite, 3TC-triphosphate. • Competes with deoxycytidine triphosphate (dCTP) for binding to reverse transcriptase and incorporation of the nucleoside analogue into viral DNA results in the termination. • 3TC-TP is a weak inhibitor of mammalian DNA polymerases α, β, and γ. • Bioavailability (F): 86%. 20
  21. 21. Lamivudine (3TC) cont… • CSF Levels: 13% of serum levels (these levels have been shown to clear HIV RNA from CSF) • T1/2: 3-6 hours • Intracellular T1/2: 12 hours • Pregnancy: (Category C) – Crosses placenta. – Use in pregnancy is safe and well established, and effective. – When combined with Zidovudine, efficacy in preventing perinatal transmission is also well established. • rapid development of resistance, and a single point mutation on RT gene. 21
  22. 22. Lamivudine (3TC) cont… • Intracellular T1/2 – NRTIs work in the cell, duration of action is based on intracellular half-life. • Toxicity: very rare – Headache – Occasional nausea – Lactic acidosis 22
  23. 23. Tenofovir Disoproxil Fumarate (TDF) • TDF is different from nucleosides in that it has already been phosphorylated once. • T1/2: 12 to 18 hours • Intracellular T1/2: 10 to 50 hours • Pregnancy: (Category B) Crosses placenta. • Bioavailability improves with food, especially high-fat meal. • Primarily eliminated by a combination of glomerular filtration and active renal tubular secretion. • Toxicity – Headache, Nausea, diarrhea – Lactic acidosis, fatty liver – Renal insufficiency (rare) 23
  24. 24. NRTI Mitochondrial Toxicity • Inhibition of mitochondrial DNA polymerase– oxidative metabolism, – ATP generation • Implicated in lactic acidosis • Other possible manifestations: – Neuropathy (d4T, ddI) – Lipoatrophy (d4T) – Pancreatitis (ddI) – Myopathy (ZDV) – Cardiomyopathy (d4T, ZDV) 24
  25. 25. Facial Lipoatrophy: may be due mitochondrial toxicity. Not reversible, occur commonly with stavudine Facial Lipoatrophy: 25
  26. 26. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) • Nevirapine (NVP) • Efavirenz (EFV) • Delavirdine (DLV) • Etravirine 26
  27. 27. NNRTI Mechanism of Action 27
  28. 28. NNRTI Mechanism of Action cont… • NNRTIs also inhibit the viral reverse transcriptase enzyme but have a different mechanism of action compared to NRTIs. • NNRTIs bind directly to the reverse transcriptase enzyme. – Inhibit viral DNA synthesis. • Unlike the NRTI agents, NNRTIs neither compete with nucleoside triphosphates nor require phosphorylation to be active. • All are substrates for CYP3A4 and can act as inducers (nevirapine), inhibitors (delavirdine), or mixed inducers and inhibitors (efavirenz). 28
  29. 29. Efavirenz • Should be taken on an empty stomach because high-fat meal increase toxicity • metabolized by CYP3A4 and CYP2B6 to inactive metabolites • It is highly bound to albumin (~ 99%) • The principal adverse effects: dizziness, drowsiness, insomnia, headache, confusion, amnesia, agitation, delusions, depression, nightmares, euphoria and Skin rash • It is both inducer and an inhibitor of CYP3A4. • Contraindicated in pregnancy (1st trimester)!! – Known to cause birth defects 29
  30. 30. Nevirapine • oral bioavailability (90%) is not food-dependent • It is extensively metabolized by the CYP3A isoform • When initiating therapy, gradual dose escalation over 14 days is recommended to decrease the incidence of rash • Hepatotoxicity occurs in about 4% of patients. • a moderate inducer of CYP3A metabolism. • Rash occurs in approximately 17% of patients 30
  31. 31. Nevirapine: Moderate Rash 31
  32. 32. Nevirapine: Severe Rash 32
  33. 33. Protease Inhibitors (PIs) • • • • • • • • • • Lopinavir Nelfinavir Indinavir Saquinavir Ritonavir Amprenavir Atazanavir Fosamprenavir Tipranavir Darunavir 33
  34. 34. Protease Inhibitors (PIs) cont… • Protease inhibitors – prevent viral protease enzyme from cleaving the polyprotein precursor to viral coat protein and reduces activation of critical viral proteins/enzymes. • Thus new virons are formed, but are defective and cannot infect other cells. • Use of PIs is associated with a syndrome of redistribution and accumulation of body fat that results in central obesity to the exception of atazanavir. 34
  35. 35. PI Mechanism of Action 35
  36. 36. PI Mechanism of Action • Protease enzyme – responsible for cleaving (cutting up) larger polyproteins into structural proteins and reverse transcriptase enzyme. • Protease is needed to form a fully mature, functional virus that is able to replicate and produce more virus • Protease inhibitors prevent this enzyme from doing its job in the later steps of the viral life cycle 36
  37. 37. PI Class Side Effects • Metabolic Disorders – Hepatotoxicities – Hyperglycemia, insulin resistance – Lipid abnormalities – Fat redistribution • Bone Disorders • GI intolerance • Drug interactions • CYP450 3A4 Inhibition – RTV > IDV = NFV = APV >SQV 37
  38. 38. Lopinavir/Ritonavir • Combination in which subtherapeutic doses of ritonavir inhibit the CYP3A4-mediated metabolism of lopinavir. • Ritonavir is acting as a pharmacokinetic enhancer rather than an antiretroviral agent. • Absorption of lopinavir is enhanced with food • Lopinavir is extensively metabolized by the CYP3A isozyme. • Toxicity – Nausea, – diarrhea – Lipid abnormalities – Hyperglycemia 38
  39. 39. Ritonavir • an inhibitor of HIV-1 and HIV-2 proteases • Metabolized by 3A4 > 2D6 • Ritonavir potent inhibitor of liver enzymes, especially CYP450 3A4. – CYP3A4 inhibitory properties exploited to prolong the half-life of more potent and less toxic PI agents. • Ritonavir is rarely used as a single PI anymore b/c of its side effect profile. • Instead, it is more often combined with other PIs to take advantage of its pharmacokinetic inhibitory properties. • Toxicity – GI intolerance – Tingling around mouth, bitter taste in mouth – Hepatitis, use with caution in hepatic impairment – Lipodystrophy, lipid abnormalities 39
  40. 40. Fat redistribution “Buffalo Hump” Central Obesity 40
  41. 41. Fat redistribution Lipoatrophy 41
  42. 42. Fusion Inhibitors • Include: Enfuvirtide • Inhibits entry of HIV into the CD4 cell. • binds to glycoprotein gp41 (a protein on the viral membrane). – prevents a change in the shape of the membrane protein and prevents fusion of the virus and the CD4 cell membrane. – blocks entry into the cell • A synthetic 36-amino-acid peptide • Unfortunately, Enfuvirtide is only active when injected subcutaneously. • This aspect (in addition to its high cost) severely limits its use in the correctional setting. • Enfuvirtide lacks cross-resistance to the other currently approved antiretroviral drug classes. 42
  43. 43. Maraviroc • First in new class of agents, CCR5 inhibitors • Approved August 6th, 2007 • Maraviroc binds to the CCR5 receptor on the membrane of human cells such as CD4 cells. – prevents the interaction of HIV-1 gp120 and human CCR5 which is necessary for entry into the cell. • Does not prevent HIV-1 entry into CXCR4-tropic or dual-tropic cells. • Indicated (in combination with other ARVs) treatment-experienced adult HIV-infected patients • Not recommended in patients who have dual/mixed tropic or CXCR4-tropic virus • Use of maraviroc should be based on treatment history and tropism assay results. 43
  44. 44. Intergrase Inhibitors: Raltegravir • A pyrimidinone analog that binds and inhibits the enzyme integrase. – It inhibits strand transfer, • Bioavailability does not appear to be food-dependent • Metabolized by glucuronidation. 44
  45. 45. Ethiopian ARV Guidelines (2008) - First-line Regimens Recommended ARV Regimens for Adults and Adolescents: Preferred : TDF+FTC/3TC+EFV = Triple FDC ZDV+3TC+EFV = ZDV/3TC + EFV ZDV+3TC+NVP = Triple FDC Alternatives: D4T/3TC/EFV = Double FDC (d4T/3TC) + EFV TDF/3TC/NVP D4T/3TC/NVP = Triple FDC ABC/3TC/EFV ABC/3TC/NVP ABC/3TC/ZDV = ZDV/3TC + ABC 45
  46. 46. Second-line Regimens Recommended ARV Regimens for Adults and Adolescents: First-line Regimen Second-line Regimen TDF+FTC/3TC+EFV/NVP ZDV+3TC+LPV/r/ATV/r or ZDV+ABC+LPV/r/ATV/r d4T+3TC+EFV/NVP TDF+3TC+/-ZDV+LPV/r/ATV/r or ABC+ ddI+ LPV/r/ATV/r ABC + 3TC + ZDV EFV/NVP + LPV/r/ATV/r 46
  47. 47. PMTCT ARVs decrease risk of MTCT by two mechanisms: 1. By reducing the viral load in the mother ARVs block viral replication →↓Viral load in the body→↑CD4cells →Improved maternal immunity 2. By preventing the virus from fixing itself in the infant 47
  48. 48. Table: Three options for PMTCT programmes (WHO 2012) a Recommended in WHO 2010 PMTCT guidelines b True only for EFV-based first-line ART; NVP-based ART not recommended for prophylaxis (CD4 >350) c Formal recommendations for Option B+ have not been made, but presumably ART would start at 48 diagnosis.
  49. 49. Reading Assignments • Chemotherapy of protozoal infections • Antifungals • Anthelmintics 49

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