Human Immunodeficiency Virus
• HIV is a Retrovirus which means:
– It contains a single-stranded RNA genome
– HIV will inco...
Immunity
Macrophages
Natural killer cells

lymphocytes

T CELLS
CLONE

B CELLS
PROLIFERATE

ANTIGEN DESTRUCTION
(INNATE IM...
Disease staging system for HIV
According to the WHO
• Stage I- infection asymptomatic and not categorized as
AIDS, expect ...
Symptoms
• The Majority of Symptoms of an HIV infection do not
show up until the disease has already begun to
damage the i...
• General symptoms :
–
–
–
–
–
–
–
–

Lack of energy
Weight loss
Frequent fevers
Sweats
Persistent or frequent fungal infe...
Opportunistic Infections
• HIV infection is usually discovered when a patient is
diagnosed with an unusually severe or per...
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 in...
HIV replication
Drug treatment for HIV
• Currently no vaccine, no cure
• Mostly drugs are postponing complications of
acquired immunodefic...
Goals of Treatment
•
•
•
•
•
•
•

Improve quality of life
Reduce HIV-related morbidity and mortality
Restore and/or preser...
Anti-HIV drugs
• Nucleoside reverse transcriptase inhibitors
(NRTIs)
• Nucleotide Reverse Transcriptase Inhibitors
(NtRTIs...
DRUG THERAPY OF HIV INFECTION
• Entry /Fusion inhibitor
Enfuvirtide
• Nucleoside reverse transcriptase inhibitors (NRTIS)
...
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 f...
Nucleoside reverse transcriptase inhibitors (NRTIS)
• 1985 – research on anti-viral medication begins
• 1987 – First drug ...
General therapeutic uses
• Generally used in combination with other drugs
(PIs) to avoid devp. of resistance (NRTI)
• Mult...
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 ly...
•
•
•
•
•

Clinical uses:↓mortality & opportunistic infections
gain weight
better quality of life
delays signs and symptom...
Lamivudine
• Deoxycytidine analogue
• Inhibits reverse transcriptase and DNA
polymerase in HBV.
• Systemic toxicity is low...
• Other nucleoside analogs: Didanosine, Stavudine,
Zalcitabine
(MOA is same as zidovudine)
• Zalcitabine is no longer used...
NRTIs
Drug

Oral Bv

Distribution/PB

Half life

Zidovidine

60-65%

All tissues 35-38%

1-3

Stavudine

85-90%

Less PB

...
Nucleotide Reverse Transcriptase Inhibitors (NtRTIs)

Tenofovir
• In the same class of drugs as NRTIs
• These are not requ...
Non-Nucleoside Reverse Transcriptase
Inhibitors (NNRTIs)
• Inhibitors of the viral enzyme reverse transcriptase
• The drug...
Nevirapine
•
•
•
•
•

Binding to RT and direct inhibition at a site
Used in combination.
Main adverse effect is rash (75%)...
NNRTIs
Drug

Oral BV

Distribution/PB

Half life

Nevirapine

90-95

Wide, CSF 45%
PB 60%

25-30

Efavirenz

50

CSF 1%
PB...
Protease Inhibitors
• Reduces the number of new of infection in
susceptible cells
• To be effective must be prolonged, pro...
Protease inhibitor
• Drugs :
• Saquinavir
• Ritonavir
• Indinavir
• Nelfinavir

• Mechanism: inhibit precursor molecules
c...
Protease Inhibitors
• These work by competitive inhibition of the viral
enzyme protease
• These drugs irreversibly bind to...
PIs
Drug

BV

Distribution/ PB

Half life

Saquinavir -S

13

Wide, 97% PB

11

ritonavir

75

98% PB

3-5

Lopinavir

Var...
Adverse Effects: PIs
• All PIs:
– Hyperlipidemia
– Lipodystrophy
– Hepatotoxicity
– GI intolerance
– Possibility of increa...
Fusion Inhibitors
• Newest Class of Drugs
• This drug binds to the glycoprotein gp41 in the
viral envelope inhibiting its ...
Fusion Inhibitors vs. Other Classes of Drugs
Adverse Effects: Fusion
Inhibitor
• ENF
– Injection-site reactions
– Increased risk of bacterial pneumonia

January 2011

...
Popular drug combinations
•
•
•
•
•
•

Indinavir+ Zidovidine+ Lamivudine
Nelfinavir+ Zidovidine+ Diadinosine
Saquinavir+ Z...
Combinations should not be use
• Atazanvir + Indinavir: Inc. unconjugated hyperbilirubinemia

• Didanosine/ Stavudine+ Zal...
13. anti retroviral
13. anti retroviral
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  • Chemokinecoreceptors
  • 13. anti retroviral

    1. 1. 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
    2. 2. 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
    3. 3. 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
    4. 4. 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
    5. 5. • 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
    6. 6. 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.
    7. 7. Retrovirus gp140 gp 41 integrease Protease RT Core proteins
    8. 8. 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
    9. 9. HIV replication
    10. 10. Drug treatment for HIV • Currently no vaccine, no cure • Mostly drugs are postponing complications of acquired immunodeficiency syndrome & AIDS related complications .
    11. 11. 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
    12. 12. Anti-HIV drugs • Nucleoside reverse transcriptase inhibitors (NRTIs) • Nucleotide Reverse Transcriptase Inhibitors (NtRTIs) • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) • Protease inhibitor ( PI ) • Fusion inhibitor
    13. 13. 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
    14. 14. Newer drugs • CCR 5 chemokine receptor inhibitor: Maraviroc • Integrase inhibitors : Raltegravir
    15. 15. 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
    16. 16. 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
    17. 17. 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)
    18. 18. Adverse Effects: NRTIs • All NRTIs: – Lactic acidosis and hepatomegaly due to mitochondrial damage – Lipodystrophy
    19. 19. 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
    20. 20. • • • • • 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
    21. 21. 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
    22. 22. • 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
    23. 23. 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
    24. 24. 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)
    25. 25. 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
    26. 26. 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.
    27. 27. 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
    28. 28. 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).
    29. 29. Protease inhibitor • Drugs : • Saquinavir • Ritonavir • Indinavir • Nelfinavir • Mechanism: inhibit precursor molecules convert to mature virions during HIV replication
    30. 30. 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
    31. 31. 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
    32. 32. 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
    33. 33. 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
    34. 34. Fusion Inhibitors vs. Other Classes of Drugs
    35. 35. Adverse Effects: Fusion Inhibitor • ENF – Injection-site reactions – Increased risk of bacterial pneumonia January 2011 36 www.aidsetc.org
    36. 36. Popular drug combinations • • • • • • Indinavir+ Zidovidine+ Lamivudine Nelfinavir+ Zidovidine+ Diadinosine Saquinavir+ Zidovidine+ Zalcitabine Ritonavir + Lopinavir + Stavudine + Lamivudine Ritonavir+ Indinavir + Stavudine + Diadinosine Amprenavir + Zidovidine+ Lamivudine
    37. 37. 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
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