13. anti retroviral
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13. anti retroviral






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  • Chemokinecoreceptors

13. anti retroviral 13. anti retroviral Presentation Transcript

  • Human Immunodeficiency Virus • HIV is a Retrovirus which means: – It contains a single-stranded RNA genome – HIV will incorporate it’s genome into it’s host cell – hijack the normal functions of the cell to replicate – This process will eventually lead to cell destruction • The target for HIV is the CD-4+ Helper T-Cells, which are the backbone of the immune system. • First recognized in 1981 June 5th
  • Immunity Macrophages Natural killer cells lymphocytes T CELLS CLONE B CELLS PROLIFERATE ANTIGEN DESTRUCTION (INNATE IMMUNITY) IgG IgM IgA, E, D SUPPRESOR (CD8) CYTOTOXIC (CD8) cellmediated immunity HELPER(CD4) Humoral
  • Disease staging system for HIV According to the WHO • Stage I- infection asymptomatic and not categorized as AIDS, expect presence of lymphadenopathy • Stage II- Minor mucocutaneous infections and recurrent URTI • Stage III- Unexplained chronic diarrhea for longer than 1month, weight loss, several bacterial infections, pulmonary infections • Stage IV- Toxoplasmosis of the brain, candidiasis of esophagous, trachea, bronchi, lungs. All of indicate AIDS View slide
  • Symptoms • The Majority of Symptoms of an HIV infection do not show up until the disease has already begun to damage the immune system • The incubation time for an HIV infection can be several weeks to several years View slide
  • • General symptoms : – – – – – – – – Lack of energy Weight loss Frequent fevers Sweats Persistent or frequent fungal infections Persistent skin rashes Flakey skin and mouth, Genital or anal sores from Herpes infections
  • Opportunistic Infections • HIV infection is usually discovered when a patient is diagnosed with an unusually severe or persistent infection • Opportunistic infections include: – Bacterial, Fungal, Parasitic, and Viral Infections • These infections will be more severe because the person’s immune system suppressed.
  • Retrovirus gp140 gp 41 integrease Protease RT Core proteins
  • Replication rate 1010/day, 109 CD cells destroyed , half life 1-2h in plasma, 1.5days in infected CD cells, in latently infected cells 12months
  • HIV replication
  • Drug treatment for HIV • Currently no vaccine, no cure • Mostly drugs are postponing complications of acquired immunodeficiency syndrome & AIDS related complications .
  • Goals of Treatment • • • • • • • Improve quality of life Reduce HIV-related morbidity and mortality Restore and/or preserve immunologic function Maximally and durably suppress HIV viral load Prevent HIV transmission Inc. CD4 count Dec. drug resistance • Inc. 5-8yr of life span January 2011 11 www.aidsetc.org
  • Anti-HIV drugs • Nucleoside reverse transcriptase inhibitors (NRTIs) • Nucleotide Reverse Transcriptase Inhibitors (NtRTIs) • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) • Protease inhibitor ( PI ) • Fusion inhibitor
  • DRUG THERAPY OF HIV INFECTION • Entry /Fusion inhibitor Enfuvirtide • Nucleoside reverse transcriptase inhibitors (NRTIS) Zidovidine Stavudine Lamivudine Abacavir Zalcitabine Didanosine Emtricitabine • Non Nucleoside reverse transcriptase inhibitors (NNRTIS) Efavirenz Nevirapine Delaviridine • Necleotide reverse transcriptase inhibitors (NTRTIS) Tenofovir • Protease Inhibitors(PIs) Saquinvir Indanavir Nelfinvir Amprenavir Ritonavir Lopinavir Atazanavir Fosamprenavir
  • Newer drugs • CCR 5 chemokine receptor inhibitor: Maraviroc • Integrase inhibitors : Raltegravir
  • Problems with drug therapy • • • • • Majority drugs have serious adverse effects More drug interaction Have to be taken for life long HIV can’t be eradicated HIV viruses have high mutation rate, cross resistance • Many drugs block the infection of the new cells rather than treating the already infected cells
  • Nucleoside reverse transcriptase inhibitors (NRTIS) • 1985 – research on anti-viral medication begins • 1987 – First drug Zidovudine produced – First NRTI – Early life extending properties General mechanism • First converted into triphosphate derivatives by host cell kinase enzymes • NRTIs are phosphorylated three times after they enter the cell to become successful inhibitors
  • General therapeutic uses • Generally used in combination with other drugs (PIs) to avoid devp. of resistance (NRTI) • Multi drug therapy is need to counter act • Combination synergetic action • Sequential blockade • Highly Active Anti Retroviral Therapy(HAART) NRTIs(2) + PI Or NRTIs(1) + NNRTIs(1) + PI(1) Or NRTIs(1) + NNRTIs(1) + PI(2)
  • Adverse Effects: NRTIs • All NRTIs: – Lactic acidosis and hepatomegaly due to mitochondrial damage – Lipodystrophy
  • zidovudine • Zidovudine first drug. • Approved by the FDA on March 20, 1987 and is thymidine analogue (HIV1 &2, T- cell lympho trophic virus) • Inhibits RT and causes chain termination • Used for post exposure prophylaxis • It reduces the incidence of neonatal HIV infection (100mg , 5 times a day) to HIV infected mother after 14weeks of gestation until birth • New born receive syrup 2mg/kg 6hrly from birth to six week of age
  • • • • • • Clinical uses:↓mortality & opportunistic infections gain weight better quality of life delays signs and symptoms of AIDS • Adverse effect: • Toxicity: Bone marrow suppression – Granulocytopenia and anemia: 45% – Severe headache, nausea, insomnia, myalgias
  • Lamivudine • Deoxycytidine analogue • Inhibits reverse transcriptase and DNA polymerase in HBV. • Systemic toxicity is low, and is well tolerated. • Resistance rapid • Used in combination with other ARVs • Chronic hepatitis B(100mgOD), HIV 1 & 2 (150mg/BD) • Zalcitabine, Lamivudine inactive each other
  • • Other nucleoside analogs: Didanosine, Stavudine, Zalcitabine (MOA is same as zidovudine) • Zalcitabine is no longer used due to its neurotoxic effects • Didanosine : Purine analogue, acid liable, dose depended pancreatitis • Stavudine : Thymidine analogue (30-40mg BD) peripheral neuropathy Lamvidine + zudovidine synergetic action
  • NRTIs Drug Oral Bv Distribution/PB Half life Zidovidine 60-65% All tissues 35-38% 1-3 Stavudine 85-90% Less PB 1.2 Lamivudine 85-90% CSF 20% 35%PB 5-7 Abacavir 83% CSF33%, 50% PB 1.5 Zalcitabine >80% CSF 20%,< 4% PB 2 Emtricitabine 93 <4% PB 10 diadanoside 42 CSF 20%,< 5% PB 1.5
  • Nucleotide Reverse Transcriptase Inhibitors (NtRTIs) Tenofovir • In the same class of drugs as NRTIs • These are not required to be phosphorylated after they enter the cell. • ADENOSINE analogue • Pro drug hydrolyzed in liver • Same mechanism of action as NTRIs • 300mg once daily after meals • Used in combination with NRTIs and PI • Toxicity: rash • Contraindication :- Used with caution in renal disease patients (stone formation)
  • Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) • Inhibitors of the viral enzyme reverse transcriptase • The drug binds to the viral enzyme at other than the active site • changes the conformation of the active site so dec. enzyme’s affinity for nucleoside binding. • This class of drugs works by non-competitive inhibition
  • Nevirapine • • • • • Binding to RT and direct inhibition at a site Used in combination. Main adverse effect is rash (75%). More potent against HIV-I. Single dose 200mg can prevents the transmission of HIV from mother to newborn when administrate to women at onset of labour. • Followed by oral dose of 2mg/kg to neonate with in 3days of delivery.
  • NNRTIs Drug Oral BV Distribution/PB Half life Nevirapine 90-95 Wide, CSF 45% PB 60% 25-30 Efavirenz 50 CSF 1% PB 99% 40-45 Delavirdine (only for HIV I) 85 CSF 0.4% PB 98% 6
  • Protease Inhibitors • Reduces the number of new of infection in susceptible cells • To be effective must be prolonged, profound and constant. • Pharmacokinetics important to maintain constant concentrations within the effective range • Metabolic adverse effects (DM, hyperglycemia) and GI (diarrhea, pain vomiting).
  • Protease inhibitor • Drugs : • Saquinavir • Ritonavir • Indinavir • Nelfinavir • Mechanism: inhibit precursor molecules convert to mature virions during HIV replication
  • Protease Inhibitors • These work by competitive inhibition of the viral enzyme protease • These drugs irreversibly bind to the active site of protease preventing it from completing the maturation of the virion • Core is produced by proteolytic cleavage of HIV gag and pol polyprotines. It inhibits maturation and function of protiens
  • PIs Drug BV Distribution/ PB Half life Saquinavir -S 13 Wide, 97% PB 11 ritonavir 75 98% PB 3-5 Lopinavir Variable 98-99% PB 5-6 Nelfonavir Variable 98-99% PB 4-5 Indinavir 65 CSF 76% , PB 60% 1.8 Amprenavir 63 90% PB 7-11 Atazanavir >70 CSF 76% , PB 86% 7
  • Adverse Effects: PIs • All PIs: – Hyperlipidemia – Lipodystrophy – Hepatotoxicity – GI intolerance – Possibility of increased bleeding risk for hemophiliacs – Drug-drug interactions January 2011 33 www.aidsetc.org
  • Fusion Inhibitors • Newest Class of Drugs • This drug binds to the glycoprotein gp41 in the viral envelope inhibiting its fusion with the CD4+ receptor on the host cell and thus preventing the cell’s infection. • Usually used as a last line option for most patient because it is only available as an injection and its high cost
  • Fusion Inhibitors vs. Other Classes of Drugs
  • Adverse Effects: Fusion Inhibitor • ENF – Injection-site reactions – Increased risk of bacterial pneumonia January 2011 36 www.aidsetc.org
  • Popular drug combinations • • • • • • Indinavir+ Zidovidine+ Lamivudine Nelfinavir+ Zidovidine+ Diadinosine Saquinavir+ Zidovidine+ Zalcitabine Ritonavir + Lopinavir + Stavudine + Lamivudine Ritonavir+ Indinavir + Stavudine + Diadinosine Amprenavir + Zidovidine+ Lamivudine
  • Combinations should not be use • Atazanvir + Indinavir: Inc. unconjugated hyperbilirubinemia • Didanosine/ Stavudine+ Zalcitabine: peripheral neuropathy • Lamivudine+ Zalcitabine: In vitro antagonism • Zidovidine+ Stavudine: Pharmacological antagonism both compete for phosphorylation